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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/
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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
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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
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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
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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]. The Ministry of Health and family welfare, India has 44 45 distributed centchroman at a subsidized cost since 1995 (social marketing scheme) [6, on September 26, 2021 by guest. Protected copyright. 46 3]. 47 48 In 2008, HLL Lifecare entered the international market by launching centchroman as 49 50 a post-coital pill under the brand name Ivyfemme in Peru, South America [9]. 51 52 However, in 2010 the license to sell the pill was revoked by Peru’s Directorate 53 General of supplies and drugs. The reason given for this was that the pill acted by 54 55 preventing implantation of a fertilized egg and sale of any abortifacient drug was 56 57 considered illegal in Peru [9]. In 2013, HLL Lifecare launched centchroman as a post- 58 coital pill in India under the brand name Tatkal-72 [10]. The production of Tatkal-72 59 60 was discontinued in 2014 due to restrictions on marketing and advertising of 4
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emergency contraceptive pills in India. BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 The Ministry of Health and family welfare, India in April 2016 decided to expand oral 6 7 contraceptive options by including centchroman in the National family planning 8 program under the brand name Chhaya [4, 5, 11]. Chhaya will be available to women 9 10 through the public delivery system and will be free of cost. Oral contraceptives that 11 12 are safe among breastfeeding women have a better potential to improve the use of 13 14 family planning methods by postpartum women, hence centchroman was included in 15 the National family planning program. 16 17 Figure 1 depicts the key milestones in the evolution of centchroman in India. 18 For peer review only 19 Figure 1: Key milestones on evolution of centchroman 20 21 In this review we have focused on the use of centchroman as an oral contraceptive pill 22 (weekly pill and post-coital pill). As a weekly contraceptive pill, the recommended 23 24 dosage of centchroman is a 30 mg pill twice a week for twelve weeks followed by a 25 26 30 mg pill once a week [4, 5]. Centchroman as an emergency post-coital pill is taken 27 as a 60 mg dose within 72 hours of intercourse [12]. 28 29 We are conducting this scoping review to determine the scope/ coverage of the body 30 31 of literature on effectiveness, safety, pharmacokinetics and mechanism of action of 32 33 centchroman as a contraceptive pill (weekly and post-coital). This review will identify 34 and map the types of available evidence on centchroman as a contraceptive pill and 35 36 determine any knowledge gaps 37 http://bmjopen.bmj.com/ 38 1.1 Aim & Objectives 39 This scoping review aims to systematically include the entire range of published and 40 41 grey literature on: 42 43 Extent and type of evidence on effectiveness and side effects of using 44 45 centchroman as a contraceptive pill (weekly and post-coital pill). on September 26, 2021 by guest. Protected copyright. 46 47 Extent of evidence on mechanism of action of centchroman when used as a 48 contraceptive in women. 49 50 Extent of evidence on pharmacokinetics of centchroman among both non- 51 52 lactating and breastfeeding women. 53 54 55 2. MATERIALS AND METHODS 56 57 A protocol for this scoping review was developed a priori using the Arksey and 58 59 O’Malley York’s five-stage framework [13]. The 5 steps of the scoping review were: 60
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(1) identifying the research question; (2) identifying the search strategy; (3) study BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 selection; (4) data charting; and (5) collating, summarizing and reporting the results. 6 7 Step 1: Identification of the research question 8 This scoping review was conducted to answer the following primary research 9 10 question: What is the current state of evidence on effectiveness and side effects of 11 12 centchroman as a contraceptive pill (weekly pill and post-coital pill)? The secondary 13 14 research questions were: What is current available evidence on mechanism of action 15 of centchroman in women? What is current evidence on pharmacokinetics of 16 17 centchroman in breastfeeding women and non-lactating women? 18 For peer review only 19 Step 2: Identification of relevant studies (Search strategy) 20 21 To address the research questions, we developed a detailed search strategy to identify 22 all relevant publications on centchroman. The following MeSH (Medical Education 23 24 Subject Headings) terms were identified and used: centchroman, ormeloxifene, saheli, 25 26 safety, pharmacokinetics, effectiveness, efficacy, and mechanism of action. Using the 27 search terms, we systematically searched the following electronic databases: 28 29 MEDLINE, EMBASE, INDMED, Cochrane library, and Google scholar for studies 30 31 published between 1970 up to 27th July 2017. The search was most recently re-run on 32 rd 33 23 January 2019 (no new studies added). 34 No limits were placed on the searches. An example of the search strategy in Embase 35 36 is given below: “ 'centchroman'/exp OR '1 [2 [4 (7 methoxy 2, 2 dimethyl 3 37 http://bmjopen.bmj.com/ 38 phenylchroman 4 yl) phenoxy] ethyl] pyrrolidine':ti,ab,de OR '2, 2 dimethyl 3 phenyl 39 40 4 [4 (2 pyrrolidinoethoxy) phenyl] 7 methoxychroman':ti,ab,de OR '3, 4 trans 2, 2 41 dimethyl 3 phenyl 4 [4 (2 pyrrolidinoethoxy) phenyl] 7 methoxychroman':ti,ab,de OR 42 43 '7 methoxy 2, 2 dimethyl 3 phenyl 4 [4 (2 pyrrolidin 1 ylethoxy) phenyl] 44 45 chroman':ti,ab,de OR 'centron':ti,ab,de OR 'choice 7':ti,ab,de OR on September 26, 2021 by guest. Protected copyright. 46 'levormeloxifene':ti,ab,de OR 'ormeloxifene':ti,ab,de OR 'saheh':ti,ab,de OR 47 48 'saheli':ti,ab,de OR 'shaeli':ti,ab,de OR 'trans 2, 2 dimethyl 3 phenyl 4 [4 (2 49 50 pyrrolidinoethoxy) phenyl] 7 methoxychroman':ti,ab,de OR ‘centchroman’:ti,ab,de 51 52 OR ‘31477-60-8’:rn”. 53 Furthermore, websites such as CDRI (Central Drug Research Institute), ICMR (Indian 54 55 Council of Medical Research), clinical trial registry of India, WHO, and Popline were 56 57 searched for studies and scientific reports on centchroman. We searched websites of 58 two major drug authorities: FDA (Food and Drug Administration) and EMA 59 60 (European Medicines Agency) and found no information on the relationship of 6
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ormeloxifene/ centchroman and oral contraceptive were available on these websites. BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 In addition, we searched for conference proceedings, and student master’s and PhD 6 7 thesis. The reference lists of all the retrieved studies were searched to identify any 8 additional studies of relevance. We contacted authors to provide studies and 9 10 additional information that was unavailable. 11 12 Step 3: Selection of studies for review 13 14 We included studies from 1970 to present (2019), to reflect the period during which 15 centchroman was first synthesized and drug trials initiated. No limits were placed on 16 17 language and location of study. We included studies on women using centchroman 18 For peer review only 19 only as a contraceptive pill (weekly pill or emergency post-coital pill). Table 1 depicts 20 21 the eligibility criteria. 22 Table 1: Inclusion/ exclusion criteria 23 24 Criteria Inclusion Exclusion 25 Study design Quantitative, qualitative and mixed Studies on animals, narrative review 26 methods study, systematic review 27 Location Any country None 28 Date 1970- Present (2019) Before 1970 29 Language All languages None 30 Research focus Main focus on safety, side effects, Main focus on non-contraceptive uses 31 effectiveness, mechanism of action and of centchroman 32 pharmacokinetics, when used as a 33 contraceptive 34 Document type Case reports, scientific reports, primary Narrative reviews, newspaper and 35 research article, systematic reviews, magazine articles. 36 commentaries, letter to editors, 37 conference proceedings, Masters and http://bmjopen.bmj.com/ PhD thesis 38 39 40 After running the search, all the retrieved studies were exported into EndNote X7 41 42 reference management software. The EndNote program was used to check for 43 44 duplication. The study selection process consisted of two levels of screening: 45 on September 26, 2021 by guest. Protected copyright. 46 (1) Title and abstract review: Two reviewers (RK, KPA) independently screened the 47 title and abstract of all the retrieved citations for inclusion guided by the eligibility 48 49 criteria. An article that was considered relevant by either or both the reviewers were 50 51 included for full text review, and any discrepancies were resolved through discussion. 52 Full text articles that were excluded at the screening stage had reasons for exclusions 53 54 documented. 55 56 (2) Full text review: In the second step, the reviewers (RK, KPA) independently 57 58 assessed the full text articles to determine if they met the inclusion and exclusion 59 criteria. Any disagreement was resolved by mutual discussions between the reviewers. 60
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For included studies, two authors (RK, KPA) extracted the data using the data- BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 charting sheet. 6 7 Step 4: Charting the Data 8 A data-charting sheet was designed in Microsoft Excel to extract the general 9 10 characteristics of each study. Information retrieved included study characteristics 11 12 (authors, country, region, year published, study aim, study design, number of 13 14 participants), key research topic (side effects, effectiveness, mechanism of action or 15 pharmacokinetics of centchroman). For each research topic separate data charting 16 17 sheets were used to extract relevant information from each included study. The data 18 For peer review only 19 charting sheets were constantly updated through the review process. 20 21 Step 5: Collating, summarizing and reporting the results 22 To summarize the findings for this scoping review, each author repeatedly reviewed 23 24 the extracted evidence independently. The extracted data was summarized based on 25 26 the individual research questions and around the following outcomes: effectiveness 27 and side effects when used as a weekly or post-coital contraceptive pill, and 28 29 mechanism of action as contraceptive pill in women and pharmacokinetics of 30 31 centchroman in non-lactating women and in breast-feeding women. The data 32 33 extracted in the data-charting sheet was analyzed descriptively (frequencies and 34 percentages) to facilitate categorization, charting and discussion. Scoping reviews 35 36 aimed to identify, map findings and to provide an overview of the available literature 37 http://bmjopen.bmj.com/ 38 in the topic area rather than an assessment of study quality [14]. 39 40 41 3. RESULTS 42 43 Of the 664 articles initially identified by our search criteria, only 33 met the inclusion 44 45 criteria for this scoping review (figure 2). Of these 33 studies, twenty-one (64%) were on September 26, 2021 by guest. Protected copyright. 46 experimental (20 non-randomized clinical trials and 1 randomized controlled trial), 47 48 four (12%) were observational (descriptive studies), three (9%) were case reports, 49 50 three (9%) were National guidelines and two (6%) were annual reports. 51 Figure 2: Prisma flow chart 52 53 54 We identified 8 studies on effectiveness of centchroman as a weekly contraceptive 55 56 pill, 1 study on effectiveness of centchroman as a post-coital pill, 13 studies on side 57 58 effects of centchroman (weekly and post-coital pill), 2 on mechanism of action in 59 60
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women and 12 studies on pharmacokinetics among non-lactating and breast-feeding BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 women. 6 7 All studies were conducted in India and reported in English. The earliest study was 8 published in 1976 and the latest in 2017. The full texts of studies were available for 9 10 all except one study for which only the abstract was available [29]. Research 11 12 publications on centchroman have increased in frequency in the recent years with 13 14 39.4% of studies published in the last 10 years (2007 – 2017) and 60.6% in the 15 previous 30-year period (1976-2006). Roughly half (54.5%) of the studies were 16 17 published from the developers of the pill (CDRI), and all were clinical trials. The 18 For peer review only 19 general characteristics of the included studies are detailed in table 2. 20 21 22 Table 2: General characteristics of included studies 23 S.no Study Author/ Year Sample Purpose Outcome 24 design size 25 1. Roy S. et al* 8 Clinical trial -To study the ovulation inducing action Mechanism 26 (1976) [15] of centchroman in anovulatory women of action Clinical trials Clinical 27 2. Chandra H. a) 40 Clinical trial -To determine the maximum tolerated Side effects et* al (1977) b) 28 dose of centchroman in human volunteers and to find 28 [16] out any toxic effects the study was carried out in 2 29 parts a) single dose study b) multiple dose study 30 3. Vaidya R. et 10 Clinical trial -To evaluate various clinical and Mechanism 31 al* (1977) hormonal parameters during immediate pre-therapy of action, 32 [17] and the first therapy cycle for evaluating its effect on Side effects 33 hypothalamic-pituitary-ovarian axis 4. Srivastava - Clinical trial -To study the binding of centchroman to Pharmacoki 34 A.K. et al* steroid binding proteins in human plasma netics 35 (1984) [18] 36 5. Nityanand S. a) Till Multicentric trial Phase III - To determine the Effectivenes 37 et al* (1988) Nov contraceptive efficacy of centchroman in a s (weekly), http://bmjopen.bmj.com/ 38 [19] 1986 multicentric trial of centchroman with 30 mg weekly Side effects 39 - 648 dose. The study reports results in two parts: a) Phase 40 April III clinical trial till November 1986 b) extended phase 1987- Nov III trials (April 1987- November 1988) 41 1988- 100 42 6. Puri V. et al* 467 Clinical trial -To determine the contraceptive efficacy Effectivenes 43 (1988)[20] of centchroman in a multicentric trial in a 30 mg s (weekly), 44 weekly dose. This paper reports results upto June Side effects 45 1984 on September 26, 2021 by guest. Protected copyright. 46 7. Paliwal J.K. 2 Clinical trial -To determine pharmacokinetics after a Pharmacoki 47 et* al (1989) 60 mg oral dose of centchroman in normal healthy netics [21] women 48 8. Nityanand S. 377 Multicentric trial- a) To study the efficacy of Effectivenes 49 et al* (1994) centchroman in a biweekly cum weekly mode of s (weekly), 50 [22] administration; b) To establish the safety of this Side effects 51 dosage schedule by serial ultrasounds. 52 9. Paliwal J.K. et 3 Clinical trial -To determine pharmacokinetics of Pharmacoki 53 al* (1994) centchroman in serum and breast milk among three netics 54 [23] nursing women 10. Gupta R.C. et 13 Clinical trial -To assess peak and trough levels of Pharmacoki 55 al* (1995) centchroman in breast milk and serum after a single netics 56 [24] 30 mg dose and after a 30 mg twice a week dose for 57 12 weeks and to calculate quantity ingested by infants 58 11. Lal J. et al* 11 Clinical trial -To determine pharmacokinetics of Pharmacoki 59 (1995) [25] centchroman after a single 30 mg dose in healthy netics 60 women
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1 2 3 BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 12. Nityanand S. a) 277 Clinical trial -a) To study the effect of centchroman Pharmacoki 5 et al* (1995) b) 57 on ovaries, b) to determine reversibility and effect on netics 6 [26] 3 progeny among centchroman users, c) to study 7 whether it is safe to administer centchroman to lactating women 8 13. Gupta R.C. et 4 Clinical trial -To assess pharmacokinetics of Pharmacoki 9 al* (1996) centchroman in maternal serum & breast milk in netics 10 [27] nursing women after a single 30 mg tablet of 11 centchroman 12 14. Lal J. et al* 6 Clinical trial -To compare the bioavailability of two Pharmacoki 13 (1996) [28] pharmaceutically equivalent brands of centchroman netics 14 tablets: Saheli vs. Centron (double blind-cross over study) 15 15. Lal J. et al* 3 Clinical trial -To study the pharmacokinetic profile Pharmacoki 16 (1998) [29] following the recommended dosage profile in normal netics 17 healthy women 18 16. KhuranaFor M. et peer2 Clinical review trial -To determine theonly extent of protein Pharmacoki 19 al* (1999) binding of centchroman at 1 and 10 /ml concentration netics 20 [30] in drug free human serum samples 21 17. Lal J. et al* 60 Clinical trial -To assess the pharmacokinetic Pharmacoki (2001) [31] parameters of centchroman with dosing schedule of netics 22 single 60 mg loading dose followed by 30 mg weekly 23 doses. To assess steady state minimum concentration 24 of centchroman after 6 different 30 mg dosing 25 schedules 26 18. Khurana M. et 17 Clinical trial -To evaluate the tissue/ serum ratio of Pharmacoki 27 al* (2002) centchroman in uterus at the maximum drug netics 28 [32] concentration 19. ICMR (2009- 720 (439 Phase IV multicentric study to evaluate the efficacy Effectivenes 29 10) [33] centchrom and side effects of centchroman s (weekly) 30 an and 31 381 for 32 Cu-T) 33 20. ICMR (2010- 2087 Update of the phase IV multicentric study on Effectivenes 34 11) [34] (934 with centchroman s (weekly) 35 centchrom an and 36 1153 with 37 Cu-T) http://bmjopen.bmj.com/ 38 21. Mittal S. et al 150 To investigate the use of centchroman as an effective Effectivenes 39 (2008) [35] method of emergency contraception and to compare s (post-
40 RCT its efficacy and side effects with single and double coital pill), 41 dose of levonorgestrel regimen Side effects 22. Tandon D. 17 To study the effect of centchroman on biochemical Effectivenes 42 (1992) [36] profile, ovulation and ovarian size (duration-12 s (weekly), 43 months) Side effects 44 23. Ghosh S. 27 To assess the pattern of usage of oral contraceptive Effectivenes 45 (2014) [37] pills in a hospital setting (duration- 8 months) s (weekly), on September 26, 2021 by guest. Protected copyright. 46 Side effects 47 24. Nair H.S. et al 153 To study the effectiveness of centchroman as Effectivenes 48 (2016) [38] contraceptive, to study possible causes of s (weekly), centchroman failure, and to study incidence of side Side effects 49 Descriptive study effects of centchroman (duration- 12 months) 50 25. Agrawal P. et 25 To study the adverse drug reactions of centchroman Side effects 51 al (2016) [39] used for contraceptive purpose (duration-12 months) 52 26. Malhotra K.P. 1 Case of young women using centchroman for a long Side effects 53 et al (2011) duration in an unsupervised fashion, presenting with 54 [40] menorrhagia 55 27. Agarwal R. et 1 Case of a women using centchroman for 10 years in Side effects 56 al (2014) [41] an unsupervised manner, presenting with abnormal uterine bleeding and enlarged uterus. 57 28. Padmaja A. et 1 Case of an unmarried 18 year women on Side effects 58 Case report al (2013) [42] unsupervised 60 mg centchroman twice weekly (for 59 menorrhagia) for 2 years, presents with c/o excess 60 menstrual flow
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1 2 3 29. MoH& FW, - Reference manual for oral contraceptive pills - BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 Government 5 of India 6 (2016) [4] 7 30. MoH& FW, - Guidelines on contraceptives: An update on new - Government family planning methods for ASHA workers 8 of India 9 (2017)[43] 10 31. manual MoH & FW, - Contraceptive updates-reference manual for doctors - 11 Government on doses, advantages and side effects. The 12 of India Government of India has planned to organize series 13 (2005)[44] of ‘contraception updates’ seminars for doctors in 14 Reference National Guideline/ public and private health care sector, to help standardize delivery of information. 15 32. Population - Report on spacing methods for family planning - 16 foundation of 17 India (2014) 18 [2] For peer review only 19 33. CSIR-Central - Annual report of CSIR, which includes unique - 20 drug research features of centchroman and details of its inclusion in 21 Annual Report institute the National family planning program, India (2017) [45] 22 23 3.1 MECHANISM OF ACTION OF CENTCHROMAN 24 Two clinical trials in our review report the mechanism of action of centchroman 25 26 among women [15, 17]. The first study was conducted among 8 women with 27 28 ovulatory failure. The women were non-randomly allocated into one of three- 29 treatment arms, where centchroman was administered in doses of 15, 30 or 60 mg 30 31 daily for 10 to 20 days [15]. Increase levels of plasma progesterone, urinary 32 33 pregnanediol and estrogen were observed reflecting that centchroman stimulates the 34 35 pituitary ovarian axis. The authors concluded that centchroman could induce 36
ovulation in anovulatory women. The second study was conducted among 10 healthy http://bmjopen.bmj.com/ 37 38 women, non-randomly allocated into 2 groups. Six women received 120 mg/week and 39 40 four women received 60mg/week schedule for two months. Increase in cycle length 41 was noticed in all cases probably due to lengthening of the follicular phase. The 42 43 authors concluded that centchroman at the mentioned doses does not seem to inhibit 44 45 ovulation although it may delay it; it exerts its contraceptive effect mainly due to its on September 26, 2021 by guest. Protected copyright. 46 47 action on cervical mucus and endometrial affecting sperm transport and implantation 48 [17]. 49 50 Animal studies demonstrated that centchroman acts by increasing the speed of 51 52 transport of the zygote through the fallopian tubes, so that it reaches the uterus early. 53 54 Secondly, it accelerates blastocyst formation, so that it’s hyper-mature when it 55 reaches the endometrium and fails to implant. Lastly, it acts by inhibiting endometrial 56 57 receptivity to blastocyst signals and by suppressing endometrial proliferation and 58 59 defective endometrial decidualization, so that it is not adequately prepared to receive 60
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a fertilized egg when it reaches the uterus [2, 4, 6, 45]. BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 3.2 PHARMACOKINETICS OF CENTCHROMAN 6 7 3.2.1 In non-lactating women 8 Five clinical trials conducted by CDRI report the pharmacokinetics of centchroman in 9 10 non-lactating women [21, 25, 28, 29, 31]. Of these, two trials report pharmacokinetics 11 12 after administration of single 30 mg dose of centchroman [25, 28], blood samples 13 14 were collected at regular intervals upto 672 hours post drug administration in both, 15 one trial reported pharmacokinetics following administration of single 60 mg dose, 16 17 blood samples were collected at regular intervals upto 504 hours post drug 18 For peer review only 19 administration [21] and one trial described pharmacokinetics after 60 mg loading dose 20 21 followed by 30 mg weekly dose [31]. In addition, one trial reported pharmacokinetics 22 following administration of 30 mg biweekly for 12 weeks (only study abstract 23 24 available) [29]. 25 26 The peak serum concentration (Cmax) of centchroman was reported by three of these 27 studies [25, 29, 31]. Cmax following a 30 mg dose is nearly half of that observed with 28 29 a 60 mg dose, indicating Cmax is dose dependent [25]. The time taken to reach the 30 31 peak (Tmax) following 30 mg or 60 mg dose was between 4 to 8 hours. In the multiple 32 33 dose study [31], it was noted that Cmax was the same after a single 30 mg dose and 34 repeated dosing did not alter the C or T [29]. This indicated that there was no 35 max max 36 accumulation of centchroman in the body with repeated doses. 37 http://bmjopen.bmj.com/ 38 The steady state minimum concentration of centchroman (Cmin) was reported in two 39 40 studies [22, 31]. The Cmin following single 30 mg dose was 16 ng/ml and it was 41 almost twice following 30 mg twice-weekly dose at 28 ng/ml, indicating it is dose- 42 43 dependent. The Cmin at 336 hours was similar to Cmin at day 80, showing the steady 44 th 45 state concentration of the drug was achieved at 5 30 mg dose [29]. on September 26, 2021 by guest. Protected copyright. 46 Centchroman is widely distributed in the body due to its high lipid solubility. The 47 48 volume of distribution and drug clearance following a 30 mg or a 60 mg dose are 49 50 comparable, suggesting that they are dose-independent [21, 25]. One study on the 51 52 distribution of centchroman in the endometrium, following a 30 mg single dose 53 reports that centchroman is rapidly absorbed and distributed to the endometrium and 54 55 at any given time, the concentration of centchroman in the uterus is 1.93 times higher 56 57 than the corresponding levels in the serum [32]. 58 Two clinical trials report the binding of centchroman to plasma proteins [18, 30]. 59 60 These show that centchroman binds strongly to serum albumin in healthy women. It 12
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has a low affinity, high capacity binding with a dissociation (Kd) rate constant of BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 13.19 X 10-6M. The binding increases with an increase in protein content. 6 7 Centchroman is metabolized in the liver into active and inactive metabolites; the 8 active metabolite (7-desmethyl centchroman) is responsible for anti-implantation 9 10 effect [31]. 11 12 3.2.2 In breast feeding women 13 14 Four clinical trials report pharmacokinetics of centchroman in breast-feeding women 15 [23, 24, 26, 27]. These studies report the infant is exposed to a small percentage (2.5% 16 17 to 9.5%) of the maternal dose of centchroman through breast milk. The Cmax in breast 18 For peer review only 19 milk was higher than Cmax in the serum, and the Tmax was attained later in the milk 20 21 than in the serum. 22 3.3 CENTCHROMAN AS POST-COITAL CONTRACEPTIVE PILL 23 24 One randomized controlled trial among 150 women reports the effectiveness of 25 26 centchroman as post-coital pill within 120 hours of single unprotected intercourse 27 [35]. The aim of this trial was to compare the efficacy and side effects of two different 28 29 centchroman regimens with 1.5 mg single dose levonorgestrel. In this trial, women 30 31 were randomly allocated into three groups (50 women in each group). Women in 32 33 Group I received a 1.5 mg single dose of levonorgestrel tablet, single 60 mg dose 34 Group II and Group III received one 30 mg tablet, twice a day at an interval of 12 35 36 hours. The side effects reported from groups I, II and III were menstrual delay > 7 37 http://bmjopen.bmj.com/ 38 days (6%, 6.2%, 2%), headache (8%, 10.6%, 14.3%), abdominal pain (2%, 6.3%, 39 40 8.2%), nausea (14%, 4.3%, 4%) respectively and 10% in group I reported dizziness. 41 Four percent in group I, 2% users in Group II and 6% users in Group III reported 42 43 pregnancies, all classified as method failure (MF) (effectiveness 96%, 98%, 94%). 44 45 This trial concluded that single dose centchroman regimen (group II) is well on September 26, 2021 by guest. Protected copyright. 46 compared to single dose regimen of levonorgestrel both in terms of efficacy and 47 48 safety. 49 50 3.4 EFFECTIVENESS OF CENTCHROMAN AS A WEEKLY 51 52 CONTRACEPTIVE 53 Eight studies (5 clinical trials and 3 observational studies) included in the scoping 54 55 review, report the effectiveness of centchroman [19, 20, 22, 33, 34, 36, 37, 38] (Table 56 57 3). Effectiveness in the included studies was calculated from the number of 58 pregnancies from method failure (MF). Any pregnancy associated with non- 59 60 compliance of the drug is classified as user failure (UF) 13
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Clinical trials: BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 Four of these studies report the results from the phase III and phase IV trials on 6 7 centchroman. The first study is a multicentric phase III clinical trial (till June 1984), 8 conducted among 467 women across 10 family welfare centers [20]. Centchroman 9 10 was administered as a 30 mg once a week tablet starting on the first day of the 11 12 menses, and thereafter one tablet was taken on the same day every subsequent week. 13 14 An additional tablet had to be taken on the first day of every subsequent menstrual 15 cycle irrespective of the weekly tablet. Women had regular check-ups every month. 16 17 The duration of centchroman use in this trial ranged from 1 month to 36 months. A 18 For peer review only 19 total of 19 MF and 44 UF pregnancies occurred during the study duration (95.9% 20 21 effective). Of the 19 MF pregnancies, 14 (73.7%) occurred in the first 6 months of 22 centchroman use and only one (5.3%) after one year of drug use (Pearl index 4.2). 23 24 The 44 UF pregnancies occurred because the women did not adhere to the pill 25 26 schedule, with 20 pregnancies (45.5%) occurring in first 6 months, 15 pregnancies 27 (34%) between 7 to 12 months and 9 pregnancies (20.5%) after one year of pill use. 28 29 Table 3: Summary of studies on effectiveness of centchroman as a weekly contraceptive pill 30 Ref* Dosage Sample Pearl Method User Effectiveness 31 size index Failure Failure 32 33 Clinical trials 34 35 20 30 mg once a week. 1st 467 4.2 19 (4.1%) 44 (9.4%) 95.9% 36 tablet on first day of 37 menses and thereafter http://bmjopen.bmj.com/ 38 one tablet on that day 39 every week. One 40 19 additional tablet was 648 3.7 27(4.2%) 66(10.2% 95.8% ) 41 taken on first day of 42 every subsequent 43 menses irrespective of weekly tablet (phase 44 100 1.2 - - -
III) on September 26, 2021 by guest. Protected copyright. 45 46 22 30 mg twice a week for 377 1.83 6 (1.6%) 24 (6.7%) 98.4% 47 3 months, followed by 48 30 mg once a week 49 50 51 52 33 30 mg twice a week for 755 (out of n.a. 20 (2.6%) - 97.4% 53 3 months, followed by 934) 54 & 30 mg once a week 55 56 34 57 58 Observational studies 59 60
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38 30 mg twice a week for 153 2 7 (4.6%) 4 (2.6%) 95.4% BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 3 months, followed by 5 36 30 mg once a week 17 0 0 0 100% 6 7 37 27 n.a. Ineffective in 2 users 93% 8 (7%) 9 10 * The complete study titles are in the reference section. 11 12 The second study is an extension of the phase III multicentric clinical trial, and 13 14 reports the results in two parts: a) phase III trial till November 1986 and b) extended 15 phase III clinical trial (April 1987 to November 1988) [19]. In the study (till 1986), 16 17 648 women were recruited from 10 family welfare centres. The dosage schedule of 18 For peer review only 19 centchroman was same as the phase III trial [20]. The duration of pill use ranged from 20 21 1 month to 52 months. Twenty-seven MF and 66 UF pregnancies occurred in the 22 study duration (95.8% effective)/ pearl index of 3.7. Among the 27 MF pregnancies, 23 24 19 (70%) occurred in the first 5 months and 4 (15%) occurred after one year of 25 26 centchroman use. For the extended phase (April 1987 to November 1988), 100 27 28 women were recruited in 5 additional centres. The details of number of pregnancies in 29 the extended phase are unavailable, however pearl index is reported as 1.2. 30 31 Phase IV clinical trial (post-marketing trial) was initiated in 2009, across 18 Human 32 33 reproductive research centers (HRRC) of ICMR, India [33, 34]. It was a non- 34 randomized clinical trial; with Cu-T users being the comparison group. The dosage 35 36 schedule for phase IV was 30 mg centchroman twice a week for 12 weeks followed 37 http://bmjopen.bmj.com/ 38 by once weekly 30 mg thereafter. The trial enrolled 2087 women (934 with 39 40 centchroman and 1153 with Cu-T). The interim results of this phase (on 755 41 centchroman users) reveal 20 MF pregnancies (97.4% effective). The detailed results 42 43 of this phase are neither published nor available on request. 44 45 One conference paper [22] reports a clinical trial among 377 women to study the on September 26, 2021 by guest. Protected copyright. 46 47 effectiveness of centchroman using the schedule: 30 mg centchroman twice a week 48 for 12 weeks followed by 30 mg once a week. The study duration ranged from 1 to 27 49 50 months. 6 MF and 24 UF were reported during the study duration (effectiveness: 51 52 98.4%). Of the 6 MF, 2 (33%) failures occurred during the first month, 2 (33%) at 3 53 months and one (17%) each at 9 and 15 months. 54 55 Observational studies: 56 57 Additionally, three observational studies report effectiveness of centchroman ranging 58 59 between 93-100% (table 3). In the first study, 153 women were followed up for 12 60
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months, of which 11 women became pregnant (4.6% MF and 2.6% UF). Majority BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 (81%) of pregnancies occurred during first 6 months while all occurred within 9 6 7 months of initiation of the pill [38]. 8 In the second study, 27 women were followed up for 8 months; effectiveness was 9 10 93% [37]. The authors did not report details of MF or UF. In the third study, 17 11 12 women were followed for 12 months; effectiveness was 100% [36]. 13 14 3.5 SIDE EFFECTS OF CENTCHROMAN USE 15 Thirteen studies [16, 17, 19, 20, 22, 35, 36, 37, 38, 39, 40, 41, 42] report side effects 16 17 from centchroman use as a weekly contraceptive pill (Table 4 and 5). We are 18 For peer review only 19 reporting frequently reported side effects under the following headings: menstrual 20 21 irregularities, other side effects, and changes on ultrasound examination. 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
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1 2 3 4 5 Table 4: Summary of studies on other side effects with centchroman use 6 Ref.* Sample Duration of use (dosage) Nausea/ Headache Backache Giddiness Abdomina Fever Low Breast 7 size vomiting l pain Hemoglobin tenderness 8 16 23 Phase I trial: Single dose of dose ranging from Yes Yes No Yes No No No No 9 5-320mg 10 28 30 days (either 60 or 120 mg) No Yes Yes (7.1%) Yes (7.1%) No Yes No No 11 (10.7%) (7.1%) 12 40 1 7 years (30 mg weekly once)For peerNo reviewNo No onlyNo No No Yes No 13 (5gm/dl) 14 35 Group Single dose (group 1: 60 mg, group2: 30 mg Yes Yes No No Yes No No Yes 15 1: 49 two tabs taken 12 hours apart) Group 1: Group 1: 5 Group 1: 3 Group 2: 1
16 Group 2 (4.3%); (10.6%); (6.3%);http://bmjopen.bmj.com/ (2%) 17 2: 47 Group 2: Group 2: 7 Group 2: 4 18 2 (4%) (14.3%) (8.2%) 19 17 Group 2 months (group A: 120 mg/ week, group B: No No No No No No No No 20 A: 6 60 mg/ week) 21 Group 22 B: 4 23 41 1 10 years (30 mg) No No No No No No Yes No
24 on September 26, 2021 by guest. Protected copyright. (4gm/dl) 25 38 153 100%- 3 months, 97% - 6 months, 93%- 9 Yes Yes No Yes No No No No 26 months, 85%- 12 months (30 mg twice weekly 1 (0.7%) 1 (0.7%) 2 (1.3%) 27 for 3 months followed by weekly 30 mg) 28 39 25 12 months (30 mg twice weekly for 3 months No No No Yes No No No 29 followed by weekly 30 mg) At 3 months: 2 (8%) 30 At 6 months: 3 (12%) 31 42 1 24 months (60 mg twice weekly for 3 months No No No No No No Yes No 32 followed by weekly 30 mg) (7gm/dl) 33 37 27 1-6 months- 18, 7-12 months-6, >12 months - No Yes No Yes Yes No Yes No 34 3 (30 mg twice weekly for 3 months followed 1 (3.7%) 1 (3.7%) 3 (11%) 35 by weekly 30 mg) 36 36 17 12 months (30 mg twice weekly for 3 months No No No No No No No No followed by weekly 30 mg) 37 20 467 30 mg once a week (phase III multicentric Yes No No No No Yes No No 38 39 40 41 42 17 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from
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1 2 3 4 5 trial up till June 1984) 1 (0.2%) 2(0.4% 6 ) 7 19 648 a. 30 mg once a week (phase III multicentric Yes Yes No Yes No No No No 8 trial till November 1986) b. and extended 1 (0.2%) 5 (0.8%) 5 (0.8%) 9 100 phase III trial (April 1987 to November 1988) No No No No No No No No 10 11 22 377 30 mg twice a week for 3 months, followed by No No No No No No No No 30 mg once a week 12 The complete study titles are in the referenceFor section. peer review only 13 * 14 15
16 Table 5: Summary of studies on menstrual irregularities with centchroman use http://bmjopen.bmj.com/ 17 18 Ref* Dosage of centchroman Sample Short cycle ≤ 20 Prolonged Scanty Ameno Menstrual Menstrual Menstrual Continuous 19 size days cycle > 45 bleeding (1 rrhea delay > 7 delay > 15 delay > 30 bleeding 20 days or 2 days) days days days 21 16 Phase I trial-60 mg-10 women, 120 28 60 mg: 10% - - - - 60 mg: 120 mg: - 22 mg- 8 women, placebo-10 women 120 mg: 12.5 % 10% 12.5% 23 40 30 mg once per week 1 ------100%; duration 20
24 on September 26, 2021 by guest. Protected copyright. days 25 35 Group 1: Single 60 mg 150 - - - - Group 1: 6.3% - - - 26 Group 2: two doses of 30 mg 12 hour Group 2: 2% 27 apart 28 17 Group A: 120 mg/ week 10 (A- - - - - Group A: 50% - - - 29 Group B: 60 mg / week 6, B-4) Group B: 25% 30 41 Unsupervised and irregular dose (30 1 ------100%; 31 mg) duration 45 32 days 33 38 30 mg twice a week for 3 months, 153 - 26% 12% 7% - - - 0.6% 34 followed by 30 mg once a week 35 39 30 mg twice a week for 3 months, 25 8% 16% - - - - 16% - 36 followed by 30 mg once a week 37 42 60 mg twice weekly for 3 months 1 ------100%, 38 followed by once weekly for next duration 10 39 40 41 42 18 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from
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1 2 3 4 5 three months. days 6 37 30 mg twice a week for 3 months, 27 4 women with menstrual irregularities (14.8%) 7 followed by 30 mg once a week 8 36 30 mg twice a week for 3 months, 17 - 3% 37.6% - - - - 1% 9 followed by 30 mg once a week 10 20 30 mg once a week (phase III 467 5% 10% ------11 multicentric trial up till June 1984) 12 19 a. 30 mg once a week (phase III 648 4.21% 8.84% ------multicentric trial till November 1986)For peer review only 13 b. and extended phase III trial (April 14 100 4% 10% ------1987 to November 1988) 15 22 30 mg twice a week for 3 months, 377 2.7% 3.7% ------
16 http://bmjopen.bmj.com/ followed by 30 mg once a week 17 The complete study titles are in the reference section. 18 * 19 20 21 3.5.1 Menstrual irregularities 22 23 The most frequent side effect among centchroman users is menstrual irregularities like: short cycles lasting < 20 days (reported by 4 studies; 4%,
24 5%, 3%, 8% users) [19, 20, 22, 39], prolonged cycles > 45 days (6 studies; 8.8%, 10%, 10%, 3%, 3.7%, 26%, on September 26, 2021 by guest. Protected copyright. 16% users) [19a, 19b, 20, 22, 36, 25 26 38, 39], scanty bleeding lasting 1 or 2 days (2 studies; 12%, 36.7% users) [36, 38], and menstrual delay > 30 days (1 study; 15 % users) [39]. 27 28 Five studies report continuous bleeding as a side effect. Of these, three are case reports of women on unsupervised long-term use of the pill, 29 30 presenting with continuous bleeding of 10 to 45 days duration [40, 41, 42]. Two other studies report continuous bleeding among 1% of 31 centchroman users [36, 38]. The Indian National guidelines on oral contraceptive use, report menstrual delay among 8% of centchroman users, 32 33 and state it typically occurs in the first three months of centchroman use [4]. 34 35 36 37 38 39 40 41 42 19 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 20 of 33
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3.5.2 Other side effects BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 The phase I trial on centchroman, initiated in 1970’s included 51 participants (23 6 7 females and 28 males) [16]. At the end of this phase, it was concluded that a dose of 8 5-320 mg centchroman is well tolerated by humans, because it did not show any 9 10 major side effect or any abnormality in laboratory parameters. 11 12 Phase III multicentric trials (till 1984) reported one women with 8 kg weight gain 13 14 over 34 months period of drug use, one of loose stools, vomiting and two with fever 15 [20]. In the phase III (till 1986) five women complained of giddiness, five of 16 17 headache, one of anorexia, one of loose motions and vomiting and one ectopic 18 For peer review only 19 pregnancy [19]. 20 21 The other side effects reported from included studies were: headache (2 studies; 1% 22 and 4% users) [37, 38], giddiness (2 studies; 1.3% and 12%) [37, 38], nausea (1 study, 23 24 0.7%) [38], and giddiness with abdominal pain (1 study; 8% at 3 months and 12% 25 26 users at 6 months) [39]. In addition, three case reports provide detail on women with 27 complaints of continuous bleeding and on investigation are found to be severely 28 29 anemic (Hb: 4 g/dl, 5 g/dl and 7 g/dl) [40, 41, 42]. Further, an observational study 30 31 reported anemia in 11% users [37]. 32 33 3.5.3 Changes in the ovaries and uterus 34 Seven studies [26, 34, 36, 38, 40, 41, 42] in the review report the ultrasound findings 35 36 among centchroman users (table 6). The main findings reported by these studies are: 37 http://bmjopen.bmj.com/ 38 (a) Three case reports found a bulky uterus with distorted endometrial cavity [40, 42, 39 40 41]. (b) One study found ovarian enlargement among 18% of the users [38]. In 41 another study among the 175 women who were followed up for 40 months on 42 43 centchroman, 15% showed ovarian enlargement. The enlargement was unilateral, 44 45 transient and never persisted and got resolved despite centchroman therapy [26]. One on September 26, 2021 by guest. Protected copyright. 46 study among 17 women, however, showed no changes in ovaries [36]. The 47 48 preliminary results of the phase IV trial report 4 women with ovarian cysts < 5 cms 49 50 and 2 women with cysts > 5 cms [34]. 51 Table 6: Summary of studies on ultrasound findings among centchroman users 52 53 Ref* No. of women Dosage of centchroman Duration of Ultrasound findings 54 who underwent Centchroman 55 USG intake 56 40 1 30 mg once a week 7 years Enlarged uterus with well 57 delineated endometrial thickness 58 & a mixed echogenic collection 59 in a distorted endometrial cavity 60 41 1 30 mg once a week 10 years Mixed echogenic collection in a
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(irregular and distorted endometrial cavity of a BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 unsupervised) bulky uterus (101 X 84 mm). 5 Ovaries were normal 6 38 28 (of 153 30 mg twice weekly for 3-12 months 20 women had normal looking 7 participants) 3 months, followed by ovaries, 8 30 mg weekly once 4 (14.2%) women had follicular 9 cysts 10 4 (14.2%) women had corpus 11 luteal cysts 12 No cyst was bigger than 2.5-3 13 cm 14 42 1 60 mg twice weekly for 2 years Bulky uterus with 8X4 cm hyper 15 3 months followed by echoic area with increased AV 16 once weekly channels within it. 17 (unsupervised use) Endometrium was not separately 18 For peer review only made out 19 36 17 30 mg twice weekly for 12 months No significant ovarian 20 3 months followed by 30 enlargement was detected during 21 mg once weekly centchroman use 22 22 64 (of 377 30 mg twice a week for 12-30 months Two cases of enlarged ovaries 23 participants) 3 months, followed by One showed enlarged ovary at 6 24 30 mg once a week months and one at 12 months 25 In both cases, enlargement was 26 due to mature unruptured 27 follicle 28 On subsequent examination at 29 12 and 20 months, ovaries were 30 normal. 31 26 175 30 mg twice a week for Upto 40 months 15% of women had ovarian 32 3 months, followed by enlargement 33 30 mg once a week Enlargement was unilateral and 34 transient 35 * The complete study titles are in the reference section. 36 37 http://bmjopen.bmj.com/ 38 4. DISCUSSION 39 40 This is the first scoping review that systematically identified and summarized the 41 42 studies on centchroman, as a contraceptive pill. Our primary aim for this scoping 43 review was to collate the overall evidence available on the current state of knowledge 44 45 on mechanism of action, pharmacokinetics, side effects and effectiveness of on September 26, 2021 by guest. Protected copyright. 46 47 centchroman as a weekly and post-coital contraceptive pill. The methods used 48 49 throughout the different stages of the review were rigorous, transparent and the 50 process is documented in sufficient detail to replicate the research approach. In 51 52 addition, we interviewed a product manager from the pharmaceutical company that 53 54 manufactures centchroman in India to gain insight on sales and marketing of 55 56 centchroman. He said that currently centchroman is only marketed in India as a 57 weekly contraceptive pill, though in the past it has been sold as an emergency post- 58 59 coital pill and was also marketed in South America for a short period. On 60
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effectiveness, with perfect use the failure rate of centchroman was 1-2%, but with BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 typical use the failure rate increases to 6-7%. We here recognize the potential conflict 6 7 of interest, as the pharmaceutical manager may be biased in responses to boost his 8 company sales. 9 10 This scoping review identified 33 primary research papers, annual reports, theses and 11 12 national guidelines on centchroman, from India published between 1976 and 2019. 13 14 Only two studies in our review report the mechanism of action of centchroman in 15 women (sample size: 8,10) [15, 17]. 16 17 Eight studies report the effectiveness of centchroman as a weekly contraceptive pill 18 For peer review only 19 involving a total of 2544 women. The reported effectiveness ranged from 96% to 98% 20 21 in clinical trials and 93% to 100% in observational studies. This review thus suggests 22 that the effectiveness of centchroman as a weekly contraceptive is slightly lower than 23 24 what is noted as 98-99% in the Indian National guidelines [4]. Only one RCT among 25 26 150 women reports the effectiveness of Centchroman as a post-coital pill [35]. It was 27 98% effective when taken as a single 60 mg within 120 hours of unprotected 28 29 intercourse. The detailed results of phase IV trials would provide conclusive 30 31 information on effectiveness. 32 33 Thirteen studies report side effects of centchroman use as an oral contraceptive. 34 Continuous bleeding and prolonged cycles > 45 days were the two most commonly 35 36 reported side effects among centchroman users. The side effects profile is similar to 37 http://bmjopen.bmj.com/ 38 that seen with hormonal contraceptive pills. The studies on side effects are of low 39 40 quality with small sample size. The largest sample for observational studies was 153 41 women and maximum follow up was of 12 months. This limits meaningful 42 43 conclusions to be drawn. Though the phase IV drug trial included a large sample (934 44 45 users), but the detailed results of this phase are not published and were not available on September 26, 2021 by guest. Protected copyright. 46 on request hence could not be used in the review. To the best of our knowledge there 47 48 has been no published scientific trial comparing side effects of centchroman to other 49 50 safe and effective oral contraceptive pills. There is a need for studies with robust 51 52 study designs comparing centchroman with other hormonal methods. 53 The Indian National guidelines [4] have menstrual delay among 8% of the 54 55 centchroman users, and do not mention any other side effects. We suggest the 56 57 guidelines be updated to include other side effects as well, so that the health providers 58 can comprehensively counsel the women on the possible side effects during 59 60 counseling. 22
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1 2 3 4 BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 5 5. LIMITATIONS 6 7 All identified studies in this scoping review were from India. The reason for this 8 could be that centchroman is a drug developed in India and has been approved for 9 10 marketing as a contraceptive pill only in India. Although centchroman was introduced 11 12 in Peru, South America in 2008 [8], its production was stopped in 2010 [9]. 13 14 Additionally, roughly half of the studies in this review were published from the 15 developers of the drug (CDRI). 16 17 There is no detailed drug trial on use of centchroman as a post-coital contraceptive 18 For peer review only 19 pill. It was available as a post-coital contraceptive pill in the Indian market in 2013; 20 21 under the brand name Tatkal-72 [10] however was discontinued in 2014 due to 22 restrictions on marketing and advertising of emergency contraceptive pills in India. 23 24 More studies are warranted to determine its use as a post-coital contraceptive pill. 25 26 Studies on side effects of centchroman as a contraceptive pill are limited by small 27 sample size, short duration of follow-up and the fact that all studies have been 28 29 conducted in India. 30 31 6. CONCLUSIONS AND RECOMMENDATIONS 32 33 Our scoping review provides a broad and a comprehensive review of currently 34 available literature on centchroman, when used as a contraceptive pill. The review 35 36 demonstrates that despite evidence on effectiveness of centchroman, more research is 37 http://bmjopen.bmj.com/ 38 needed on side effects and mechanism of action. Insufficient evidence exists on its 39 40 use as a post-coital contraceptive pill. Robust study designs are needed such as RCT 41 or longitudinal studies to compare effectiveness and safety of centchroman with other 42 43 short-term modern contraceptives such as combined hormonal oral pills (COCs) or 44 45 progesterone only pills (POPs) contraceptives. It is clear that there are extensive gaps on September 26, 2021 by guest. Protected copyright. 46 in the literature that warrant further studies, both in Indian and International settings. 47 48 The uncertainty and diversity of side effects and effectiveness in the studies across 49 50 India, implies lack of body of evidence to make global recommendations on 51 52 centchroman, a contraceptive method that is licensed and used in the second most 53 populous country in the world. 54 55 7. ETHICAL APPROVAL AND CONSENT TO PARTICIPATE 56 57 Not applicable 58 8. CONSENT FOR PUBLICATION 59 60
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All authors read and approved the final manuscript. This review contains the BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 collective views of an international group of experts, and does not necessarily 6 7 represent the decisions or the stated policy of the World Health Organization. 8 9. COMPETING INTERESTS 9 10 The funding sources did not play a role in the study design, analysis and interpretation 11 12 of data, in the writing of the report, or in the decision to submit the article for 13 14 publication. The conclusions and opinions expressed here are those of the authors and 15 not necessarily those of the funder. 16 17 10. FUNDING 18 For peer review only 19 The UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, 20 21 Development and Research Training in Human Reproduction (HRP), a co-sponsored 22 program executed by the WHO, funded this work 23 24 11. AUTHOR’S CONTRIBUTIONS 25 26 The idea for this publication was conceived by RK and JK. RK and KPA prepared the 27 first draft. All other authors provided significant contributions to the draft. All authors 28 29 reviewed the draft manuscript and approved the final manuscript for publication. 30 31 12. ACKNOWLEDGEMENTS 32 33 We would like to thank Mr. Tomas John Allen, librarian at WHO Geneva for his 34 assistance in developing a search strategy and running the search for this scoping 35 36 review. We would like to thank Drs. Manisha Malhotra, Bulbul Sood, Saswati das 37 http://bmjopen.bmj.com/ 38 (JHPIEGO), Shalini Singh (ICMR) for their support in identifying the stakeholders 39 40 and for their valuable suggestions on the protocol and the initial draft of this scoping 41 review. We would also like to thank all the stakeholders who participated in the 42 43 interviews and shared their experiences with centchroman use. 44 45 ABBREVIATIONS on September 26, 2021 by guest. Protected copyright. 46 SRH- Sexual and reproductive health 47 48 UNFPA- United Nations Population Fund 49 50 USAID- United States Agency for International Development 51 52 WHO- World Health Organization 53 ICMR-Indian Council of Medical Research 54 55 CDRI-Central Drug Research Institute 56 57 SERM- Selective Estrogen Receptor Modulator 58 59 60
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REFERENCES: BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 1. Singh MM. Centchroman, a selective estrogen receptor modulator, as a 6 7 contraceptive and for the management of hormone-related clinical disorders. 8 Medicinal Research Reviews 2001; 21(4): 302-347. 9 10 2. Population foundation of India. Spacing methods of family planning. Available 11 12 from http://populationfoundation.in/files/fileattached/Fileattached-1492415902- 13 th 14 Family_Planning_methods_Eng.pdf. Cited 17 November 2017 15 3. Kamboj V., Ray S., Anand N. Centchroman: A safe reversible post-coital 16 17 contraceptive with curative and prophylactic activity in many disorders. Frontiers 18 For peer review only 19 in Bioscience (Elite edition) 2018; 10: 1-14 20 21 4. Family planning division, Ministry of Health and Family welfare, Government of 22 India. Reference manual for Oral contraceptive pills. New Delhi: Ministry of 23 24 Health and Family welfare -Government of India; 2016. 25 26 5. D. Balasubramanian. On conception and contraception: The story of Saheli; The 27 Hindu: 24th June 2017. Available from https://www.thehindu.com/sci- 28 29 tech/science/on-conception-and-contraception-the-story-of- 30 31 saheli/article19140909.ece. Cited 28th June 2018. 32 33 6. Lal J. Clinical pharmacokinetics and interaction of centchroman - A mini review. 34 Contraception 2010; 81(4): 275-280. 35 36 7. World Health Organization. WHO drug information: Recommended INN list 34 37 http://bmjopen.bmj.com/ 38 international nonproprietary names for pharmaceutical substances. Volume 8, 39 40 Number 4. Geneva: World Health Organization; 1994. 41 8. Chawla P.C. CSIR’s novel contraceptive drug- a woman’s true Saheli. In: Chawla 42 43 PC, editor. CSIR News: Progress, promise and prospects. New Delhi: NISCAR 44 45 Press; 2010, Volume 60 (No. 15 & 16): 171-172. on September 26, 2021 by guest. Protected copyright. 46 9. Population Research Institute. News from Latin America. One less weapon 47 48 against the unborn: The abortion pill gets pulled from market. January 1 2010. 49 50 Population Research Institute. Available from https://www.pop.org/news-from- 51 52 latin-america-one-less-weapon-against-the-unborn-the-abortion-pill-gets-pulled- 53 from-the-market/. Cited 23rd November 2017 54 55 10. HLL Lifecare Limited. Innovating for healthy generations. Annual report 2013- 56 57 2014. Available from 58 http://www.lifecarehll.com/page/render/reference/Annual_Report. Cited 20th 59 60 October 2017 25
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11. CSIR-Central drug research institute. Centchroman. Available from BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 http://cdri.res.in/centchroman.aspx. Cited 20th October 2017. 6 7 12. Hindustan Latex Family Planning Promotion Trust (HLFPPT). Tatkal-72. 8 Available from https://hlfppt.org/tatkaal-72-contraceptive-pill/. Cited 20th October 9 10 2017 11 12 13. Arksey H, O’Malley L. Scoping studies: towards a methodological framework. 13 14 International Journal of Social Research Methodology 2005; 8:19-42. 15 14. Peters M.D., Godfrey C.M., Khalil H., Mclnerney P., Parker D., Soares C.B. 16 17 Guidance for conducting systematic scoping reviews. International journal of 18 For peer review only 19 evidence- based healthcare. 2015, 13 (3):141-146. 20 21 15. Roy S., Lakshmi Kumari G., Madoiya K., Prakash V., Ray S. Induction of 22 ovulation in the Human with centchroman: a preliminary report. Fertility and 23 24 sterility 1976; 27 (9): 1108-1110. 25 26 16. Chandra H, Srimal RC, Kamboj VP. Clinical pharmacology studies with 27 centchroman. Indian Journal of Experimental Biology 1977; 15(12): 1170-1172. 28 29 17. Vaidya R, Joshi U, Meherji P. Activity profile of centchroman in healthy female 30 31 volunteers. Indian Journal of Experimental Biology 1977; 15(12): 1173-1176. 32 33 18. Srivastava AK, Agnihotri A, Kamboj VP. Binding of centchroman - a 34 nonsteroidal antifertility agent to human plasma proteins. Experientia 1984; 40 35 36 (5): 465-466. 37 http://bmjopen.bmj.com/ 38 19. Nityanand S., Chandrawati, Singh L., Srivastava J.S., Kamboj V.P. Clinical 39 40 evaluation of centchroman: A new oral contraceptive. Hormone antagonists for 41 fertility regulation, Eds: CP Puri, PFA VanLook Indian Soc Study Reprod Fert, 42 43 Bombay. 1988: 223-230. 44 45 20. Puri V., Kamboj V.P., Chandra H., Ray S., Kole P.L., Dhawan B.N. Results of on September 26, 2021 by guest. Protected copyright. 46 multicentric trial of Centchroman. Pharmacology for health in Asia, Eds: BN 47 48 Dhawan et al New Delhi: Allied Publishers. 1988: 439-447. 49 50 21. Paliwal JK, Gupta RC, Grover PK, Asthana OP, Srivastava JS, Nityanand S. High 51 52 performance liquid chromatographic (HPLC) determination of centchroman in 53 human serum and application to single-dose pharmacokinetics. Pharmaceutical 54 55 Research 1989; 6(12): 1048-1051. 56 57 22. Nityanand S. Kamboj V.P., Chandrawati, Das K., Gupta K., Rohtagi P., et al. 58 Contraceptive efficacy and safety of centchroman with biweekly-cum- weekly 59 60
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schedule. Current concepts in fertility regulation and reproduction, Eds: CP Puri, BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 PFA VanLook New Delhi, Wiley Eastern Ltd. 1994: 61-68 6 7 23. Paliwal JK, Grover PK, Asthana OP, Nityanand S, Gupta RC. Excretion of 8 centchroman in breast milk. British Journal of Clinical Pharmacology 1994; 38(5): 9 10 485-486. 11 12 24. Gupta RC, Paliwal JK, Nityanand S, Asthana OP, Lal J. Centchroman: A new 13 14 non-steroidal oral contraceptive in human milk. Contraception 1995; 52(5): 301- 15 305. 16 17 25. Lal J, Asthana OP, Nityanand S, Gupta RC: Pharmacokinetics of centchroman in 18 For peer review only 19 healthy female subjects after oral administration. Contraception 1995; 52(5): 297- 20 21 300. 22 26. Nityanand S. Gupta R.C., Kamboj V.P., Srivastava J.S., Berry M. Centchroman: 23 24 current status as a contraceptive. Indian progress in family welfare: clinical 25 26 research on maternal and child health & contraception, Eds: SC dawn, A Misra 27 Calcutta, Dawn books. 1995: 26-31. 28 29 27. Gupta RC, Nityanand S, Asthana OP, Lal J. Pharmacokinetics of centchroman in 30 31 nursing women and passage into breast milk. Clinical Drug Investigation 1996; 32 33 11(5): 305-309. 34 28. Lal J, Nityanand S, Asthana OP, Gupta RC. Comparative bioavailability of two 35 36 commercial centchroman tablets in healthy female subjects. Indian Journal of 37 http://bmjopen.bmj.com/ 38 Pharmacology 1996; 28(1): 32-34. 39 40 29. Lal J, Nityanand S., Asthana O.P., Gupta R.C. Multiple dose pharmacokinetics 41 of centchroman in female volunteers. Indian Journal of Pharmacology. 1998; 30: 42 43 120. 44 45 30. Khurana M, Paliwal JK, Kamboj VP, Gupta RC. Binding of centchroman with on September 26, 2021 by guest. Protected copyright. 46 human serum as determined by charcoal adsorption method. International Journal 47 48 of Pharmaceutics 1999; 192(2): 109-114. 49 50 31. Lal J, Nitynand S, Asthana OP, Nagaraja NV, Gupta RC: Optimization of 51 52 contraceptive dosage regimen of Centchroman. Contraception 2001; 63(1): 47-51. 53 32. Khurana M, Lal J, Kamboj M, Nityanand S, Kamboj VP, Gupta RC. Uptake of 54 55 centchroman by the human uterus. Clinical Drug Investigation 2002; 22(10): 715- 56 57 718. 58 59 60
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33. Indian Council of Medical Research (ICMR). Reproductive Health: Annual report BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 2009-10. Available from http://www.icmr.nic.in/annual/2009-10/english/rh.pdf. 6 th 7 Cited 20 November 2017 8 34. Indian Council of Medical Research (ICMR). Reproductive Health: Annual report 9 10 2010-11. Available from http://www.icmr.nic.in/annual/2010- 11 12 11/English%20Annual%20Report/rh.pdf . Cited 20th November 2017 13 14 35. Mittal S, Sehgal R, Jindal VI, Sikka P, Kandpal S, Maiti L, Kumar A. Single dose 15 levonorgestrel and two regimens of centchroman for emergency contraception. 16 17 Journal of the Turkish German Gynecology Association 2008; 9(3): 132-137. 18 For peer review only 19 36. Tandon D. Effect of centchroman on biochemical profile, ovulation and ovarian 20 21 size. Masters of Surgery Thesis. Bundelkhand University. 1992. Available from 22 https://ia601601.us.archive.org/16/items/in.ernet.dli.2015.269787/2015.269787.Ef 23 24 fect-Of.pdf 25 26 37. Ghosh S. Prospective observational study of the pattern of usage of oral 27 contraceptive pills. Masters of Pharmacy thesis. 2014. Available from 28 29 http://jadunivdspace.jdvu.ac.in/bitstream/123456789/29440/1/Acc.%20No.%20D 30 31 C%201823.pdf 32 33 38. Nair HS, Jayasimhan P. A prospective study of centchroman users with special 34 reference to its contraceptive benefit. Journal of evidence based medicine and 35 36 healthcare. 2016; 3 (98): 5374-5380. 37 http://bmjopen.bmj.com/ 38 39. Agrawal P, Kushwa V, Mangal BK. Evaluation of safety profile of centchroman 39 40 for contraceptive purpose. National journal of medical and allied sciences. 2016; 41 5(2): 41-44. 42 43 40. Malhotra KP, Sherpa M, Bhatia A. Centchroman: Is unsupervised long-term use 44 45 warranted? Case report. European Journal of Contraception and Reproductive on September 26, 2021 by guest. Protected copyright. 46 Health Care 2011; 16(5): 403-406. 47 48 41. Agarwal R., Radhakrishnan G, Radhika AG, Grover A. Abnormal uterine bleed- 49 50 an adverse event of long-term centchroman use? Indian journal of maternal and 51 52 child health 2014; 16(2): 1-7. 53 42. Padmaja A, Vemulapalli P, Jaya Prada Devi K. Rare case of endometrial 54 55 hyperplasia following unsupervised prolonged use of ormeloxifene. IOSR Journal 56 57 of dental and medical sciences. 2013; 5(4): 55-57 58 59 60
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43. Family planning division, Ministry of Health and Family welfare, Government of BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 India. An update on new family planning methods for ASHA. New Delhi: 6 7 Ministry of Health and Family welfare -Government of India; 2017. 8 44. Ministry of Health and family welfare, Government of India, United Nations 9 10 Population Fund. Contraceptive updates. Reference manual for doctors. New 11 12 Delhi: Ministry of Health and Family welfare; 2005. 13 14 45. Central drug research institute, Lucknow. Annual report 2016-17. Available from 15 http://www.cdri.res.in/Annual_Reports/Annual_Report_2016_17.pdf. Cited 21st 16 17 October 2017 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
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1 2 3 Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for 4 Scoping Reviews (PRISMA-ScR) Checklist 5 6 REPORTED SECTION ITEM PRISMA-ScR CHECKLIST ITEM 7 ON PAGE # 8 TITLE 9 Title 1 Identify the report as a scoping review. 1 10 ABSTRACT 11 Provide a structured summary that includes (as 12 applicable): background, objectives, eligibility criteria, Structured 13 2 sources of evidence, charting methods, results, and 2-3 summary 14 conclusions that relate to the review questions and 15 objectives. 16 INTRODUCTION For peer review only 17 Describe the rationale for the review in the context of what is already known. Explain why the review 18 Rationale 3 4-5 19 questions/objectives lend themselves to a scoping 20 review approach. 21 Provide an explicit statement of the questions and 22 objectives being addressed with reference to their key 23 Objectives 4 elements (e.g., population or participants, concepts, and 5 24 context) or other relevant key elements used to 25 conceptualize the review questions and/or objectives. 26 METHODS 27 Indicate whether a review protocol exists; state if and Protocol and where it can be accessed (e.g., a Web address); and if 28 5 - 29 registration available, provide registration information, including the registration number. 30 Specify characteristics of the sources of evidence used 31 Eligibility criteria 6 as eligibility criteria (e.g., years considered, language, 7 32
and publication status), and provide a rationale. http://bmjopen.bmj.com/ 33 Describe all information sources in the search (e.g., 34 Information databases with dates of coverage and contact with 7 6 35 sources* authors to identify additional sources), as well as the 36 date the most recent search was executed. 37 Present the full electronic search strategy for at least 1 38 Search 8 database, including any limits used, such that it could be 6 39 repeated. 40
Selection of on September 26, 2021 by guest. Protected copyright. State the process for selecting sources of evidence (i.e., 41 sources of 9 7 screening and eligibility) included in the scoping review. 42 evidence† 43 Describe the methods of charting data from the included 44 sources of evidence (e.g., calibrated forms or forms that 45 Data charting have been tested by the team before their use, and 10 8 46 process‡ whether data charting was done independently or in 47 duplicate) and any processes for obtaining and 48 confirming data from investigators. 49 List and define all variables for which data were sought Data items 11 8 50 and any assumptions and simplifications made. If done, provide a rationale for conducting a critical 51 Critical appraisal of appraisal of included sources of evidence; describe the 52 individual sources 12 - methods used and how this information was used in any 53 of evidence§ 54 data synthesis (if appropriate). Describe the methods of handling and summarizing the 55 Synthesis of results 13 8 56 data that were charted. 57 58 59 1 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 33 of 33 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from
1 2 3 REPORTED SECTION ITEM PRISMA-ScR CHECKLIST ITEM 4 ON PAGE # 5 RESULTS 6 Give numbers of sources of evidence screened, Selection of 7 assessed for eligibility, and included in the review, with sources of 14 8 8 reasons for exclusions at each stage, ideally using a flow evidence 9 diagram. 10 Characteristics of For each source of evidence, present characteristics for 11 sources of 15 9-11 which data were charted and provide the citations. 12 evidence 13 Critical appraisal If done, present data on critical appraisal of included within sources of 16 - 14 sources of evidence (see item 12). 15 evidence 16 Results of For peerFor each included review source of evidence, only present the 17 individual sources 17 relevant data that were charted that relate to the review 11-21 18 of evidence questions and objectives. Summarize and/or present the charting results as they 19 Synthesis of results 18 11-21 20 relate to the review questions and objectives. 21 DISCUSSION 22 Summarize the main results (including an overview of Summary of concepts, themes, and types of evidence available), link 23 19 21-22 24 evidence to the review questions and objectives, and consider the 25 relevance to key groups. 26 Limitations 20 Discuss the limitations of the scoping review process. 23 27 Provide a general interpretation of the results with 28 Conclusions 21 respect to the review questions and objectives, as well 23 as potential implications and/or next steps. 29 FUNDING 30 Describe sources of funding for the included sources of 31 evidence, as well as sources of funding for the scoping 32 Funding 22 24 review. Describe the role of the funders of the scoping http://bmjopen.bmj.com/ 33 review. 34 JBI = Joanna Briggs Institute; PRISMA-ScR = Preferred Reporting Items for Systematic reviews and Meta-Analyses 35 extension for Scoping Reviews. 36 * Where sources of evidence (see second footnote) are compiled from, such as bibliographic databases, social media 37 platforms, and Web sites. 38 † A more inclusive/heterogeneous term used to account for the different types of evidence or data sources (e.g., 39 quantitative and/or qualitative research, expert opinion, and policy documents) that may be eligible in a scoping review as opposed to only studies. This is not to be confused with information sources (see first footnote). 40
‡ The frameworks by Arksey and O’Malley (6) and Levac and colleagues (7) and the JBI guidance (4, 5) refer to the on September 26, 2021 by guest. Protected copyright. 41 process of data extraction in a scoping review as data charting. 42 § The process of systematically examining research evidence to assess its validity, results, and relevance before 43 using it to inform a decision. This term is used for items 12 and 19 instead of "risk of bias" (which is more applicable 44 to systematic reviews of interventions) to include and acknowledge the various sources of evidence that may be used 45 in a scoping review (e.g., quantitative and/or qualitative research, expert opinion, and policy document). 46 47 48 From: Tricco AC, Lillie E, Zarin W, O'Brien KK, Colquhoun H, Levac D, et al. PRISMA Extension for Scoping Reviews (PRISMA- 49 ScR): Checklist and Explanation. Ann Intern Med. ;169:467–473. doi: 10.7326/M18-0850 50 51 52 53 54 55 56 57 58 59 2 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 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.R1
Article Type: Original research
Date Submitted by the 11-Aug-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
Primary Subject http://bmjopen.bmj.com/ Reproductive medicine Heading:
Secondary Subject Heading: Obstetrics and gynaecology
Keywords: centchroman, safety, effectiveness, oral pill, contraception, ormeloxifene
on September 26, 2021 by guest. Protected copyright.
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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
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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. 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. Two studies 30 31 reported mechanism of action of centchroman. Pharmacokinetics was reported by five 32 33 studies among non-breast feeding women and four studies among breast-feeding 34 women. Eight studies reported on effectiveness ranging between 93-100%. 35 36 Pregnancies due to user failure ranged from 2.6 % to 10.2 %. Although side effects 37 http://bmjopen.bmj.com/ 38 were reported in thirteen studies, but the incidence varied greatly between the studies. 39 40 Continuous bleeding and prolonged cycles > 45 days were the most commonly 41 reported side effects. All studies conducted had a small sample size and the duration 42 43 of follow up of women was 12 months or less. Fifty five percent of studies were by 44 45 the developers of the pill (CDRI) and results of the phase IV clinical trial were on September 26, 2021 by guest. Protected copyright. 46 unavailable. 47 48 Conclusions 49 50 The scoping review shows that studies with robust designs and conducted in 51 52 international context are lacking. Insufficient evidence exists on centchroman use as a 53 post-coital contraceptive pill. The broad uncertainty in range of side effects and 54 55 effectiveness in the studies implies insufficient evidence to make global 56 57 recommendations on centchroman that is currently licensed as a contraceptive in 58 India. 59 60 KEYWORDS: Centchroman, safety, effectiveness, oral pill, contraception, 2
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Ormeloxifene. BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 Strengths and Limitations of this study 6 7 Strength of our study is that it is the first scoping review to explore the 8 mechanism of action, pharmacokinetics, effectiveness and side effects of 9 10 centchroman, when used as a weekly or post-coital contraceptive pill. 11 12 A limitation of our review is that we are likely to have missed studies on 13 14 mechanism of action of centchroman since animal studies were excluded from 15 the review. 16 17 All identified studies in this scoping review were from India. Additionally, 18 For peer review only 19 roughly half of the studies in this review were published from the developers 20 21 of the drug (CDRI). 22 There is no detailed drug trial on use of centchroman as a post-coital 23 24 contraceptive pill. 25 26 Studies on side effects of centchroman as a contraceptive pill are limited by 27 28 small sample size, short duration of follow-up and the fact that all studies have 29 been conducted in India. 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
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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 [3, 5] Centchroman (3, 4 trans-2, 2-dimethyl-3- 28 29 phenyl 4-p (β- pyrrolidinoethoxy) phenyl 7-methoxychroman) in 1967 [3, 6]. Since it 30 31 was made at CDRI and belongs to the chroman family, it was named as Centchroman. 32 33 In 1994, centchroman was given an International non-proprietary name (INN) as 34 Ormeloxifene [7]. Following pre-clinical and clinical studies (phase 1 and 2) in 1989 35 36 the Drug Controller General of India approved centchroman as an oral contraceptive 37 http://bmjopen.bmj.com/ 38 pill in 1991 [3, 6]. It was available in the Indian market since 1992. It was first 39 40 manufactured by Torrent pharmaceuticals, Ahmedabad and marketed under brand 41 name of Centron. Later Hindustan Latex Limited (HLL) Life care Limited; 42 43 Thiruvananthapuram manufactured it under the brand names Choice-7 and Saheli [8]. 44 45 The Ministry of Health and family welfare, India has distributed centchroman at a on September 26, 2021 by guest. Protected copyright. 46 subsidized cost since 1995 (social marketing scheme) [3, 6]. 47 48 In 2008, HLL Lifecare entered the international market by launching centchroman as 49 50 a post-coital pill under the brand name Ivyfemme in Peru, South America [9]. 51 52 However, in 2010 the license to sell the pill was revoked by Peru’s Directorate 53 General of supplies and drugs. The reason given for this was that the pill acted by 54 55 preventing implantation of a fertilized egg and sale of any abortifacient drug was 56 57 considered illegal in Peru [9]. In 2013, HLL Lifecare launched centchroman as a post- 58 coital pill in India under the brand name Tatkal-72 [10]. The production of Tatkal-72 59 60 was discontinued in 2014 due to restrictions on marketing and advertising of 4
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emergency contraceptive pills in India. BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 The Ministry of Health and family welfare, India in April 2016 decided to expand oral 6 7 contraceptive options by including centchroman in the National family planning 8 program under the brand name Chhaya [4, 5, 11]. Chhaya is available to women 9 10 through the public delivery system free of cost. Oral contraceptives that are safe 11 12 among breastfeeding women have a better potential to improve the use of family 13 14 planning methods by postpartum women, hence centchroman was included in the 15 National family planning program. Figure 1 depicts the key milestones in the 16 17 evolution of centchroman in India. 18 For peer review only 19 Figure 1: Key milestones on evolution of centchroman 20 21 In this review we have focused on the use of centchroman as an oral contraceptive pill 22 (weekly pill and post-coital pill). As a weekly contraceptive pill, the recommended 23 24 dosage of centchroman is a 30 mg pill twice a week for twelve weeks followed by a 25 26 30 mg pill once a week [4, 5]. Centchroman as an emergency post-coital pill is taken 27 as a 60 mg dose within 72 hours of intercourse [12]. 28 29 We are conducting this scoping review to determine the scope/ coverage of the body 30 31 of literature on effectiveness, safety, pharmacokinetics and mechanism of action of 32 33 centchroman as a contraceptive pill (weekly and post-coital). This review will identify 34 and map the types of available evidence on centchroman as a contraceptive pill and 35 36 determine any knowledge gaps 37 http://bmjopen.bmj.com/ 38 1.1 Aim & Objectives 39 This scoping review aims to systematically include the entire range of published and 40 41 grey literature on: 42 43 Extent and type of evidence on effectiveness and side effects of using 44 45 centchroman as a contraceptive pill (weekly and post-coital pill). on September 26, 2021 by guest. Protected copyright. 46 47 Extent of evidence on mechanism of action of centchroman when used as a 48 contraceptive in women. 49 50 Extent of evidence on pharmacokinetics of centchroman among both non- 51 52 lactating and breastfeeding women. 53 54 55 2. METHODS 56 57 A protocol for this scoping review was developed a priori using the Arksey and 58 59 O’Malley York’s five-stage framework [13]. The 5 steps of the scoping review were: 60
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(1) identifying the research question; (2) identifying the search strategy; (3) study BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 selection; (4) data charting; and (5) collating, summarizing and reporting the results. 6 7 Step 1: Identification of the research question 8 This scoping review was conducted to answer the following primary research 9 10 question: What is the current state of evidence on effectiveness and side effects of 11 12 centchroman as a contraceptive pill (weekly pill and post-coital pill)? The secondary 13 14 research questions were: What is current available evidence on mechanism of action 15 of centchroman in women? What is current evidence on pharmacokinetics of 16 17 centchroman in breastfeeding women and non-lactating women? 18 For peer review only 19 Step 2: Identification of relevant studies (Search strategy) 20 21 To address the research questions, we developed a detailed search strategy to identify 22 all relevant publications on centchroman. The following MeSH (Medical Education 23 24 Subject Headings) terms were identified and used: centchroman, ormeloxifene, saheli, 25 26 safety, pharmacokinetics, effectiveness, efficacy, and mechanism of action. Using the 27 search terms, we systematically searched the following electronic databases: 28 29 MEDLINE, EMBASE, INDMED, Cochrane library, and Google scholar for studies 30 31 published between 1970 up to 27th July 2017. The search was most recently re-run on 32 rd 33 23 January 2019 (no new studies added). 34 No limits were placed on the searches. An example of the search strategy in Embase 35 36 is given below: “ 'centchroman'/exp OR '1 [2 [4 (7 methoxy 2, 2 dimethyl 3 37 http://bmjopen.bmj.com/ 38 phenylchroman 4 yl) phenoxy] ethyl] pyrrolidine':ti,ab,de OR '2, 2 dimethyl 3 phenyl 39 40 4 [4 (2 pyrrolidinoethoxy) phenyl] 7 methoxychroman':ti,ab,de OR '3, 4 trans 2, 2 41 dimethyl 3 phenyl 4 [4 (2 pyrrolidinoethoxy) phenyl] 7 methoxychroman':ti,ab,de OR 42 43 '7 methoxy 2, 2 dimethyl 3 phenyl 4 [4 (2 pyrrolidin 1 ylethoxy) phenyl] 44 45 chroman':ti,ab,de OR 'centron':ti,ab,de OR 'choice 7':ti,ab,de OR on September 26, 2021 by guest. Protected copyright. 46 'levormeloxifene':ti,ab,de OR 'ormeloxifene':ti,ab,de OR 'saheh':ti,ab,de OR 47 48 'saheli':ti,ab,de OR 'shaeli':ti,ab,de OR 'trans 2, 2 dimethyl 3 phenyl 4 [4 (2 49 50 pyrrolidinoethoxy) phenyl] 7 methoxychroman':ti,ab,de OR ‘centchroman’:ti,ab,de 51 52 OR ‘31477-60-8’:rn”. 53 Furthermore, websites such as CDRI (Central Drug Research Institute), ICMR (Indian 54 55 Council of Medical Research), clinical trial registry of India, WHO, and Popline were 56 57 searched for studies and scientific reports on centchroman. We searched websites of 58 two major drug authorities: FDA (Food and Drug Administration) and EMA 59 60 (European Medicines Agency) and found no information on the relationship of 6
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ormeloxifene/ centchroman and oral contraceptive were available on these websites. BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 In addition, we searched for conference proceedings, and student master’s and PhD 6 7 thesis. The reference lists of all the retrieved studies were searched to identify any 8 additional studies of relevance. We contacted authors to provide studies and 9 10 additional information that was unavailable. 11 12 Step 3: Selection of studies for review 13 14 We included studies from 1970 to present (2019), to reflect the period during which 15 centchroman was first synthesized and drug trials initiated. No limits were placed on 16 17 language and location of study. We included studies on women using centchroman 18 For peer review only 19 only as a contraceptive pill (weekly pill or emergency post-coital pill). Table 1 depicts 20 21 the eligibility criteria. 22 Table 1: Inclusion/ exclusion criteria 23 24 Criteria Inclusion Exclusion 25 Study design Quantitative, qualitative and mixed Studies on animals, narrative review 26 methods study, systematic review 27 Location Any country None 28 Date 1970- Present (2019) Before 1970 29 Language All languages None 30 Research focus Main focus on safety, side effects, Main focus on non-contraceptive uses 31 effectiveness, mechanism of action and of centchroman 32 pharmacokinetics, when used as a 33 contraceptive 34 Document type Case reports, scientific reports, primary Narrative reviews, newspaper and 35 research article, systematic reviews, magazine articles. 36 commentaries, letter to editors, 37 conference proceedings, Masters and http://bmjopen.bmj.com/ PhD thesis 38 39 40 After running the search, all the retrieved studies were exported into EndNote X7 41 42 reference management software. The EndNote program was used to check for 43 44 duplication. The study selection process consisted of two levels of screening: 45 on September 26, 2021 by guest. Protected copyright. 46 (1) Title and abstract review: Two reviewers (RK, KPA) independently screened the 47 title and abstract of all the retrieved citations for inclusion guided by the eligibility 48 49 criteria. An article that was considered relevant by either or both the reviewers were 50 51 included for full text review, and any discrepancies were resolved through discussion. 52 Full text articles that were excluded at the screening stage had reasons for exclusions 53 54 documented. 55 56 (2) Full text review: In the second step, the reviewers (RK, KPA) independently 57 58 assessed the full text articles to determine if they met the inclusion and exclusion 59 criteria. Any disagreement was resolved by mutual discussions between the reviewers. 60
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For included studies, two authors (RK, KPA) extracted the data using the data- BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 charting sheet. 6 7 Step 4: Charting the Data 8 A data-charting sheet was designed in Microsoft Excel to extract the general 9 10 characteristics of each study. Information retrieved included study characteristics 11 12 (authors, country, region, year published, study aim, study design, number of 13 14 participants), key research topic (side effects, effectiveness, mechanism of action or 15 pharmacokinetics of centchroman). For each research topic separate data charting 16 17 sheets were used to extract relevant information from each included study. The data 18 For peer review only 19 charting sheets were constantly updated through the review process. 20 21 Step 5: Collating, summarizing and reporting the results 22 To summarize the findings for this scoping review, each author repeatedly reviewed 23 24 the extracted evidence independently. The extracted data was summarized based on 25 26 the individual research questions and around the following outcomes: effectiveness 27 and side effects when used as a weekly or post-coital contraceptive pill, and 28 29 mechanism of action as contraceptive pill in women and pharmacokinetics of 30 31 centchroman in non-lactating women and in breast-feeding women. The data 32 33 extracted in the data-charting sheet was analyzed descriptively (frequencies and 34 percentages) to facilitate categorization, charting and discussion. Scoping reviews 35 36 aimed to identify, map findings and to provide an overview of the available literature 37 http://bmjopen.bmj.com/ 38 in the topic area rather than an assessment of study quality [14]. 39 40 Patient and Public Involvement: Patients and public were not involved in this review. 41 3. RESULTS 42 43 Of the 664 articles initially identified by our search criteria, only 33 met the inclusion 44 45 criteria for this scoping review (figure 2). Of these 33 studies, twenty-one (64%) were on September 26, 2021 by guest. Protected copyright. 46 experimental (20 non-randomized clinical trials and 1 randomized controlled trial), 47 48 four (12%) were observational (descriptive studies), three (9%) were case reports, 49 50 three (9%) were National guidelines and two (6%) were annual reports. 51 Figure 2: Prisma flow chart 52 53 54 We identified 8 studies on effectiveness of centchroman as a weekly contraceptive 55 56 pill, 1 study on effectiveness of centchroman as a post-coital pill, 13 studies on side 57 58 effects of centchroman (weekly and post-coital pill), 2 on mechanism of action in 59 60
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women and 12 studies on pharmacokinetics among non-lactating and breast-feeding BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 women. 6 7 All studies were conducted in India and reported in English. The earliest study was 8 published in 1976 and the latest in 2017. The full texts of studies were available for 9 10 all except one study for which only the abstract was available [15]. Research 11 12 publications on centchroman have increased in frequency in the recent years with 13 14 39.4% of studies published in the last 10 years (2007 – 2017) and 60.6% in the 15 previous 30-year period (1976-2006). Roughly half (54.5%) of the studies were 16 17 published from the developers of the pill (CDRI), and all were clinical trials. The 18 For peer review only 19 general characteristics of the included studies are detailed in table 2. 20 21 22 Table 2: General characteristics of included studies 23 S.no Study Author/ Year Sample Purpose Outcome 24 design size 25 1. Roy S. et al* 8 To study the ovulation inducing action of Mechanism of 26 (1976) [16] centchroman in anovulatory women action 2. Chandra H. a) 40 To determine the maximum tolerated dose of Side effects
27 trials Clinical et* al (1977) b) 28 centchroman in human volunteers and to find out 28 [17] any toxic effects the study was carried out in 2 29 parts a) single dose study b) multiple dose study 30 3. Vaidya R. et 10 To evaluate various clinical and hormonal Mechanism of 31 al* (1977) parameters during immediate pre-therapy and the action, Side effects 32 [18] first therapy cycle for evaluating its effect on 33 hypothalamic-pituitary-ovarian axis 4. Srivastava - To study the binding of centchroman to steroid Pharmacokinetics 34 A.K. et al* binding proteins in human plasma 35 (1984) [19] 36 5. Nityanand S. a) Till To determine the contraceptive efficacy of Effectiveness 37 et al* (1988) Nov centchroman in a multicentric trial of (weekly), Side http://bmjopen.bmj.com/ 38 [20] 1986 centchroman with 30 mg weekly dose. The study effects 39 - 648 reports results in two parts: a) Phase III clinical 40 April trial till November 1986 b) extended phase III 1987- Nov trials (April 1987- November 1988) 41 1988- 100 42 6. Puri V. et al* 467 To determine the contraceptive efficacy of Effectiveness 43 (1988)[21] centchroman in a multicentric trial in a 30 mg (weekly), Side 44 weekly dose. This paper reports results upto June effects 45 1984 on September 26, 2021 by guest. Protected copyright. 46 7. Paliwal J.K. 2 To determine pharmacokinetics after a 60 mg oral Pharmacokinetics 47 et* al (1989) dose of centchroman in normal healthy women [22] 48 8. Nityanand S. 377 a) To study the efficacy of centchroman in a Effectiveness 49 et al* (1994) biweekly cum weekly mode of administration; b) (weekly), Side 50 [23] To establish the safety of this dosage schedule by effects 51 serial ultrasounds. 52 9. Paliwal J.K. et 3 To determine pharmacokinetics of centchroman Pharmacokinetics 53 al* (1994) in serum and breast milk among three nursing 54 [24] women 10. Gupta R.C. et 13 To assess peak and trough levels of centchroman Pharmacokinetics 55 al* (1995) in breast milk and serum after a single 30 mg 56 [25] dose and after a 30 mg twice a week dose for 12 57 weeks and to calculate quantity ingested by 58 infants 59 11. Lal J. et al* 11 To determine pharmacokinetics of centchroman Pharmacokinetics 60 (1995) [26] after a single 30 mg dose in healthy women
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1 2 3 12. Nityanand S. a) 277 a) To study the effect of centchroman on ovaries, Pharmacokinetics BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 et al* (1995) b) 57 b) to determine reversibility and effect on 5 [27] 3 progeny among centchroman users, c) to study 6 whether it is safe to administer centchroman to 7 lactating women 13. Gupta R.C. et 4 To assess pharmacokinetics of centchroman in Pharmacokinetics 8 al* (1996) maternal serum & breast milk in nursing women 9 [28] after a single 30 mg tablet of centchroman 10 14. Lal J. et al* 6 To compare the bioavailability of two Pharmacokinetics 11 (1996) [29] pharmaceutically equivalent brands of 12 centchroman tablets: Saheli vs. Centron (double 13 blind-cross over study) 14 15. Lal J. et al* 3 To study the pharmacokinetic profile following Pharmacokinetics (1998) [15] the recommended dosage profile in normal 15 healthy women 16 16. Khurana M. et 2 To determine the extent of protein binding of Pharmacokinetics 17 al* (1999) centchroman at 1 and 10 /ml concentration in 18 [30] For peerdrug freereview human serum samples only 19 17. Lal J. et al* 60 To assess the pharmacokinetic parameters of Pharmacokinetics 20 (2001) [31] centchroman with dosing schedule of single 60 21 mg loading dose followed by 30 mg weekly doses. To assess steady state minimum 22 concentration of centchroman after 6 different 30 23 mg dosing schedules 24 18. Khurana M. et 17 To evaluate the tissue/ serum ratio of Pharmacokinetics 25 al* (2002) centchroman in uterus at the maximum drug 26 [32] concentration 27 19. ICMR (2009- 720 (439 Phase IV multicentric study to evaluate the Effectiveness 28 10) [33] centchrom efficacy and side effects of centchroman (weekly) an and 29 381 for 30 Cu-T) 31 20. ICMR (2010- 2087 Update of the phase IV multicentric study on Effectiveness 32 11) [34] (934 with centchroman (weekly) 33 centchrom 34 an and 1153 with 35 Cu-T) 36 21. Mittal S. et al 150 To investigate the use of centchroman as an Effectiveness (post- 37 (2008) [35] effective method of emergency contraception and coital pill), Side http://bmjopen.bmj.com/
38 RCT to compare its efficacy and side effects with effects 39 single and double dose of levonorgestrel regimen 40 22. Tandon D. 17 To study the effect of centchroman on Effectiveness 41 (1992) [36] biochemical profile, ovulation and ovarian size (weekly), Side (duration-12 months) effects 42 23. Ghosh S. 27 To assess the pattern of usage of oral Effectiveness 43 (2014) [37] contraceptive pills in a hospital setting (duration- (weekly), Side 44 8 months) effects 45 24. Nair H.S. et al 153 To study the effectiveness of centchroman as Effectiveness on September 26, 2021 by guest. Protected copyright. 46 (2016) [38] contraceptive, to study possible causes of (weekly), Side 47 centchroman failure, and to study incidence of effects 48 Descriptive study side effects of centchroman (duration- 12 months) 25. Agrawal P. et 25 To study the adverse drug reactions of Side effects 49 al (2016) [39] centchroman used for contraceptive purpose 50 (duration-12 months) 51 26. Malhotra K.P. 1 Case of young women using centchroman for a Side effects 52 et al (2011) long duration in an unsupervised fashion, 53 [40] presenting with menorrhagia 54 27. Agarwal R. et 1 Case of a women using centchroman for 10 years Side effects 55 al (2014) [41] in an unsupervised manner, presenting with abnormal uterine bleeding and enlarged uterus. 56 28. Padmaja A. et 1 Case of an unmarried 18 year women on Side effects 57
Case report al (2013) [42] unsupervised 60 mg centchroman twice weekly 58 (for menorrhagia) for 2 years, presents with c/o 59 excess menstrual flow 60
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1 2 3 29. MoH& FW, - Reference manual for oral contraceptive pills Dosage schedule, BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 Government side effects 5 of India 6 (2016) [4] 7 30. MoH& FW, - Guidelines on contraceptives: An update on new Dosage schedule, Government family planning methods for ASHA workers benefits and side 8 of India effects 9 (2017)[43] 10 31. manual MoH & FW, - Contraceptive updates-reference manual for Mechanism of 11 Government doctors on doses, advantages and side effects. action, side effects 12 of India The Government of India has planned to organize 13 (2005)[44] series of ‘contraception updates’ seminars for 14 Reference National Guideline/ doctors in public and private health care sector, to help standardize delivery of information. 15 32. Population - Report on spacing methods for family planning Mechanism of 16 foundation of action, 17 India (2014) effectiveness, side 18 [2] For peer review only effects and 19 advantages 20 33. CSIR-Central - Annual report of CSIR, which includes unique Unique features 21 drug research features of centchroman and details of its and details of its
Annual Report institute inclusion in the National family planning inclusion in 22 (2017) [45] program, India National FP 23 program 24 3.1 MECHANISM OF ACTION OF CENTCHROMAN 25 26 Two clinical trials in our review report the mechanism of action of centchroman 27 28 among women [16, 18]. The first study was conducted among 8 women with 29 ovulatory failure. The women were non-randomly allocated into one of three- 30 31 treatment arms, where centchroman was administered in doses of 15, 30 or 60 mg 32 33 daily for 10 to 20 days [16]. Increase levels of plasma progesterone, urinary 34 35 pregnanediol and estrogen were observed reflecting that centchroman stimulates the 36
pituitary ovarian axis. The authors concluded that centchroman could induce http://bmjopen.bmj.com/ 37 38 ovulation in anovulatory women. The second study was conducted among 10 healthy 39 40 women, non-randomly allocated into 2 groups. Six women received 120 mg/week and 41 four women received 60 mg/week schedule for two months. Increase in cycle length 42 43 was noticed in all cases probably due to lengthening of the follicular phase. The 44 45 authors concluded that centchroman at the mentioned doses does not seem to inhibit on September 26, 2021 by guest. Protected copyright. 46 47 ovulation although it may delay it; it exerts its contraceptive effect mainly due to its 48 action on cervical mucus and endometrial affecting sperm transport and implantation 49 50 [18]. 51 52 Animal studies demonstrated that centchroman acts by increasing the speed of 53 54 transport of the zygote through the fallopian tubes, so that it reaches the uterus early. 55 Secondly, it accelerates blastocyst formation, so that it’s hyper-mature when it 56 57 reaches the endometrium and fails to implant. Lastly, it acts by inhibiting endometrial 58 59 receptivity to blastocyst signals and by suppressing endometrial proliferation and 60
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defective endometrial decidualization, so that it is not adequately prepared to receive BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 a fertilized egg when it reaches the uterus [2, 4, 6, 45]. 6 7 3.2 PHARMACOKINETICS OF CENTCHROMAN 8 3.2.1 In non-lactating women 9 10 Five clinical trials conducted by CDRI report the pharmacokinetics of centchroman in 11 12 non-lactating women [15, 22, 26, 29, 31]. Of these, two trials report pharmacokinetics 13 14 after administration of single 30 mg dose of centchroman [26, 29], blood samples 15 were collected at regular intervals upto 672 hours post drug administration in both, 16 17 one trial reported pharmacokinetics following administration of single 60 mg dose, 18 For peer review only 19 blood samples were collected at regular intervals upto 504 hours post drug 20 21 administration [22] and one trial described pharmacokinetics after 60 mg loading dose 22 followed by 30 mg weekly dose [31]. In addition, one trial reported pharmacokinetics 23 24 following administration of 30 mg biweekly for 12 weeks (only study abstract 25 26 available) [15]. 27 The peak serum concentration (Cmax) of centchroman was reported by three of these 28 29 studies [15, 26, 31]. Cmax following a 30 mg dose is nearly half (55.5 ± 14.5 μg/L) of 30 31 that observed with a 60 mg dose, indicating Cmax is dose dependent [26]. The time 32 33 taken to reach the peak (Tmax) following 30 mg or 60 mg dose was between 4 to 8 34 hours. In the multiple dose study, it was noted that C was the same after a single 30 35 max 36 mg dose (55 ± 14.2 ng/ml) and repeated dosing did not alter the Cmax (62.4 ± 11.9 37 http://bmjopen.bmj.com/ 38 ng/ml) or Tmax (6 h) [15]. This indicated that there was no accumulation of 39 40 centchroman in the body with repeated doses. 41 The steady state minimum concentration of centchroman (Cmin) was reported in two 42 43 studies [23, 31]. The Cmin following single 30 mg dose was 16 ng/ml and it was 44 45 almost twice following 30 mg twice-weekly dose at 28 ng/ml, indicating it is dose- on September 26, 2021 by guest. Protected copyright. 46 dependent. The C at 336 hours (25.2 ± 12.4 ng/ml) was similar to C at day 80 47 min min 48 (24.2 ± 4.8 ng/ml), showing the steady state concentration of the drug was achieved at 49 50 5th 30 mg dose [15]. 51 52 Centchroman is widely distributed in the body due to its high lipid solubility. The 53 volume of distribution and drug clearance following a 30 mg (Vd/F: 1328 ± 458 L, 54 55 Cl/F 6.35 ± 1.8 L/h) or a 60 mg dose (Vd/F: 1077 L; 1909 L, Cl/F 4.4; 7.6 L/h) are 56 57 comparable, suggesting that they are dose-independent [22, 26]. One study on the 58 distribution of centchroman in the endometrium, following a 30 mg single dose 59 60 reports that centchroman is rapidly absorbed and distributed to the endometrium and 12
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at any given time, the concentration of centchroman in the uterus (mean: 152 ± 39 BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 ng/g) is 1.93 times higher than the corresponding levels in the serum (mean: 55 ± 13 6 7 μg/L) [32]. 8 Two clinical trials report the binding of centchroman to plasma proteins [19, 30]. 9 10 These show that centchroman binds strongly to serum albumin in healthy women. It 11 12 has a low affinity, high capacity binding with a dissociation (Kd) rate constant of 13 -6 14 13.19 X 10 M. The binding increases with an increase in protein content. The trial by 15 Khurana M. et al showed that with a method that includes dilution of serum, protein 16 17 binding is found to be 95.2 ± 1.1 and 88.2 ± 2.1% at 1 and 10 μg/ml. While in method 18 For peer review only 19 II, which is devoid of any dilution, protein-binding estimates were higher at 101.8 ± 20 21 1.3 and 94.9 ± 3.6% at 1 and 10 μg/ml [30]. 22 Centchroman is metabolized in the liver into active and inactive metabolites; the 23 24 active metabolite (7-desmethyl centchroman) is responsible for anti-implantation 25 26 effect [31]. 27 3.2.2 In breast feeding women 28 29 Four clinical trials report pharmacokinetics of centchroman in breast-feeding women 30 31 [24, 25, 27, 28]. These studies report the infant is exposed to a small percentage (2.5% 32 33 to 9.5%) of the maternal dose of centchroman through breast milk. The Cmax in breast 34 milk was higher (70.7 ± 27.5 μg/L) than C in the serum (60.7 ± 12.2 μg/L), and the 35 max 36 Tmax was attained later in the milk (8.50 ± 1.7 h) than in the serum (6 h) [28]. 37 http://bmjopen.bmj.com/ 38 3.3 CENTCHROMAN AS POST-COITAL CONTRACEPTIVE PILL 39 40 One randomized controlled trial among 150 women reports the effectiveness of 41 centchroman as post-coital pill within 120 hours of single unprotected intercourse 42 43 [35]. The aim of this trial was to compare the efficacy and side effects of two different 44 45 centchroman regimens with 1.5 mg single dose levonorgestrel. In this trial, women on September 26, 2021 by guest. Protected copyright. 46 were randomly allocated into three groups (50 women in each group). Women in 47 48 Group I received a 1.5 mg single dose of levonorgestrel tablet, single 60 mg dose 49 50 Group II and Group III received one 30 mg tablet, twice a day at an interval of 12 51 52 hours. The side effects reported from groups I, II and III were menstrual delay > 7 53 days (6%, 6.2%, 2%), headache (8%, 10.6%, 14.3%), abdominal pain (2%, 6.3%, 54 55 8.2%), nausea (14%, 4.3%, 4%) respectively and 10% in group I reported dizziness. 56 57 Four percent in group I, 2% users in Group II and 6% users in Group III reported 58 pregnancies, all classified as method failure (MF) (effectiveness 96%, 98%, 94%). 59 60 This trial concluded that single dose centchroman regimen (group II) is well 13
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compared to single dose regimen of levonorgestrel both in terms of efficacy and BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 safety. 6 7 3.4 EFFECTIVENESS OF CENTCHROMAN AS A WEEKLY 8 CONTRACEPTIVE 9 10 Eight studies (5 clinical trials and 3 observational studies) included in the scoping 11 12 review, report the effectiveness of centchroman [20, 21, 23, 33, 34, 36, 37, 38] (Table 13 14 3). Effectiveness in the included studies was calculated from the number of 15 pregnancies from method failure (MF). Any pregnancy associated with non- 16 17 compliance of the drug is classified as user failure (UF). 18 For peer review only 19 Clinical trials: 20 21 Four of these studies report the results from the phase III and phase IV trials on 22 centchroman. The first study is a multicentric phase III clinical trial (till June 1984), 23 24 conducted among 467 women across 10 family welfare centers [21]. Centchroman 25 26 was administered as a 30 mg once a week tablet starting on the first day of the 27 menses, and thereafter one tablet was taken on the same day every subsequent week. 28 29 An additional tablet had to be taken on the first day of every subsequent menstrual 30 31 cycle irrespective of the weekly tablet. Women had regular check-ups every month. 32 33 The duration of centchroman use in this trial ranged from 1 month to 36 months. A 34 total of 19 MF and 44 UF pregnancies occurred during the study duration (95.9% 35 36 effective). Of the 19 MF pregnancies, 14 (73.7%) occurred in the first 6 months of 37 http://bmjopen.bmj.com/ 38 centchroman use and only one (5.3%) after one year of drug use (Pearl index 4.2). 39 40 The 44 UF pregnancies occurred because the women did not adhere to the pill 41 schedule, with 20 pregnancies (45.5%) occurring in first 6 months, 15 pregnancies 42 43 (34%) between 7 to 12 months and 9 pregnancies (20.5%) after one year of pill use. 44
Table 3: Summary of studies on effectiveness of centchroman as a weekly contraceptive pill on September 26, 2021 by guest. Protected copyright. 45 Dosage Sample Pearl Method User Effectiveness 46 Ref* size index Failure Failure 47 48 Clinical trials 49 50 21 30 mg once a week. 1st 467 4.2 19 (4.1%) 44 (9.4%) 95.9% 51 tablet on first day of 52 menses and thereafter 53 one tablet on that day 54 every week. One 55 20 additional tablet was 648 3.7 27(4.2%) 66(10.2% 95.8% 56 taken on first day of ) 57 every subsequent 58 menses irrespective of 59 weekly tablet (phase 100 1.2 - - - 60
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III) BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 23 30 mg twice a week for 377 1.83 6 (1.6%) 24 (6.7%) 98.4% 6 3 months, followed by 7 30 mg once a week 8 9 10 11 33 30 mg twice a week for 755 (out of n.a. 20 (2.6%) - 97.4% 12 3 months, followed by 934) 13 & 30 mg once a week 14 15 34 16 17 Observational studies 18 For peer review only 19 38 30 mg twice a week for 153 2 7 (4.6%) 4 (2.6%) 95.4% 20 3 months, followed by 21 36 30 mg once a week 17 0 0 0 100% 22 23 37 27 n.a. Ineffective in 2 users 93% 24 (7%) 25 26 * The complete study titles are in the reference section. 27 28 The second study is an extension of the phase III multicentric clinical trial, and 29 30 reports the results in two parts: a) phase III trial till November 1986 and b) extended 31 phase III clinical trial (April 1987 to November 1988) [20]. In the study (till 1986), 32 33 648 women were recruited from 10 family welfare centres. The dosage schedule of 34 35 centchroman was same as the phase III trial [21]. The duration of pill use ranged from 36
1 month to 52 months. Twenty-seven MF and 66 UF pregnancies occurred in the http://bmjopen.bmj.com/ 37 38 study duration (95.8% effective)/ pearl index of 3.7. Among the 27 MF pregnancies, 39 40 19 (70%) occurred in the first 5 months and 4 (15%) occurred after one year of 41 42 centchroman use. For the extended phase (April 1987 to November 1988), 100 43 women were recruited in 5 additional centres. The details of number of pregnancies in 44 45 the extended phase are unavailable, however pearl index is reported as 1.2. on September 26, 2021 by guest. Protected copyright. 46 47 Phase IV clinical trial (post-marketing trial) was initiated in 2009, across 18 Human 48 49 reproductive research centers (HRRC) of ICMR, India [33, 34]. It was a non- 50 randomized clinical trial; with Cu-T users being the comparison group. The dosage 51 52 schedule for phase IV was 30 mg centchroman twice a week for 12 weeks followed 53 54 by once weekly 30 mg thereafter. The trial enrolled 2087 women (934 with 55 centchroman and 1153 with Cu-T). The interim results of this phase (on 755 56 57 centchroman users) reveal 20 MF pregnancies (97.4% effective). The detailed results 58 59 of this phase are neither published nor available on request. 60
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One conference paper [23] reports a clinical trial among 377 women to study the BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 effectiveness of centchroman using the schedule: 30 mg centchroman twice a week 6 7 for 12 weeks followed by 30 mg once a week. The study duration ranged from 1 to 27 8 months. 6 MF and 24 UF were reported during the study duration (effectiveness: 9 10 98.4%). Of the 6 MF, 2 (33%) failures occurred during the first month, 2 (33%) at 3 11 12 months and one (17%) each at 9 and 15 months. 13 14 Observational studies: 15 Additionally, three observational studies report effectiveness of centchroman ranging 16 17 between 93-100% (table 3). In the first study, 153 women were followed up for 12 18 For peer review only 19 months, of which 11 women became pregnant (4.6% MF and 2.6% UF). Majority 20 21 (81%) of pregnancies occurred during first 6 months while all occurred within 9 22 months of initiation of the pill [38]. 23 24 In the second study, 27 women were followed up for 8 months; effectiveness was 25 26 93% [37]. The authors did not report details of MF or UF. In the third study, 17 27 women were followed for 12 months; effectiveness was 100% [36]. 28 29 3.5 SIDE EFFECTS OF CENTCHROMAN USE 30 31 Thirteen studies [17, 18, 20, 21, 23, 35, 36, 37, 38, 39, 40, 41, 42] report side effects 32 33 from centchroman use as a weekly contraceptive pill (Table 4 and 5). We are 34 reporting frequently reported side effects under the following headings: menstrual 35 36 irregularities, other side effects, and changes on ultrasound examination. 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
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1 2 3 4 5 Table 4: Summary of studies on other side effects with centchroman use (percentage of women with the side effects) 6 Ref.* Sample Duration of use (dosage) Nausea/ Headache Backache Giddiness Abdomina Fever Low Breast 7 size vomiting (%) (%) (%) l pain (%) (%) Hemoglobin tenderness 8 (%) (%) (%) 9 17 23 Phase I trial: Single dose of dose ranging from + + - + - - - - 10 5-320mg 11 28 30 days (either 60 or 120 mg) - + (10.7%) + (7.1%) + (7.1%) - + - - 12 For peer review only (7.1%) 13 40 1 7 years (30 mg weekly once) ------+ - 14 35 Group Single dose (group 1: 60 mg, group2: 30 mg + + - - + - - + 15 1: 49 two tabs taken 12 hours apart) Group Group 1: Group 1: Group 2:
16 Group 1: (10.6%); (6.3%);http://bmjopen.bmj.com/ (2%) 17 2: 47 (4.3%); Group 2: Group 2: 18 Group (14.3%) (8.2%) 19 2: (4%) 20 18 Group 2 months (group A: 120 mg/ week, group B: ------21 A: 6 60 mg/ week) 22 Group 23 B: 4
24 41 1 10 years (30 mg) - - - - - on September 26, 2021 by guest. Protected copyright. - + - 25 38 153 100%- 3 months, 97% - 6 months, 93%- 9 + + - + - - - - 26 months, 85%- 12 months (30 mg twice weekly (0.7%) (0.7%) (1.3%) 27 for 3 months followed by weekly 30 mg) 28 39 25 12 months (30 mg twice weekly for 3 months - - - + - - - 29 followed by weekly 30 mg) At 3 months: (8%) 30 At 6 months: (12%) 31 42 1 24 months (60 mg twice weekly for 3 months ------+ - 32 followed by weekly 30 mg) 33 37 27 1-6 months- 18, 7-12 months-6, >12 months - - + - + + - + - 34 3 (30 mg twice weekly for 3 months followed (3.7%) (3.7%) (11%) 35 by weekly 30 mg) 36 36 17 12 months (30 mg twice weekly for 3 months ------followed by weekly 30 mg) 37 21 467 30 mg once a week (phase III multicentric + - - - - + - - 38 39 40 41 42 17 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from
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1 2 3 4 5 trial up till June 1984) (0.2%) (0.4%) 6 20 648 a. 30 mg once a week (phase III multicentric + + - + - - - - 7 trial till November 1986) b. and extended (0.2%) (0.8%) (0.8%) 8 100 phase III trial (April 1987 to November 1988) ------9 10 23 377 30 mg twice a week for 3 months, followed by ------11 30 mg once a week 12 * The complete study titles are in the referenceFor section. peer review only 13 14 15 Table 5: Summary of studies on menstrual irregularities with centchroman use
16 http://bmjopen.bmj.com/ 17 Ref* Dosage of centchroman Sample Short cycle ≤ 20 Prolonged Scanty Ameno Menstrual Menstrual Menstrual Continuous 18 size days cycle > 45 bleeding (1 rrhea delay > 7 delay > 15 delay > 30 bleeding 19 days or 2 days) days days days 20 17 Phase I trial-60 mg-10 women, 120 28 60 mg: 10% - - - - 60 mg: 120 mg: - 21 mg- 8 women, placebo-10 women 120 mg: 12.5 % 10% 12.5% 22 40 30 mg once per week 1 ------100%; 23 duration 20 days 24 on September 26, 2021 by guest. Protected copyright. 25 35 Group 1: Single 60 mg 150 - - - - Group 1: 6.3% - - - 26 Group 2: two doses of 30 mg 12 hour Group 2: 2% 27 apart 28 18 Group A: 120 mg/ week 10 (A- - - - - Group A: 50% - - - 29 Group B: 60 mg / week 6, B-4) Group B: 25% 30 41 Unsupervised and irregular dose (30 1 ------100%; mg) duration 45 31 days 32 38 30 mg twice a week for 3 months, 153 - 26% 12% 7% - - - 0.6% 33 followed by 30 mg once a week 34 39 30 mg twice a week for 3 months, 25 8% 16% - - - - 16% - 35 followed by 30 mg once a week 36 42 60 mg twice weekly for 3 months 1 ------100%, 37 followed by once weekly for next duration 10 38 39 40 41 42 18 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from
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1 2 3 4 5 three months. days 6 37 30 mg twice a week for 3 months, 27 4 women with menstrual irregularities (14.8%) 7 followed by 30 mg once a week 8 36 30 mg twice a week for 3 months, 17 - 3% 37.6% - - - - 1% 9 followed by 30 mg once a week 10 21 30 mg once a week (phase III 467 5% 10% ------11 multicentric trial up till June 1984) 12 20 a. 30 mg once a week (phase III 648 4.21% 8.84% ------multicentric trial till November 1986)For peer review only 13 b. and extended phase III trial (April 14 100 4% 10% ------1987 to November 1988) 15 23 30 mg twice a week for 3 months, 377 2.7% 3.7% ------
16 http://bmjopen.bmj.com/ followed by 30 mg once a week 17 The complete study titles are in the reference section. 18 * 19 20 21 3.5.1 Menstrual irregularities 22 23 The most frequent side effect among centchroman users is menstrual irregularities like: short cycles lasting < 20 days (reported by 4 studies; 4%,
24 5%, 3%, 8% users) [20, 21, 23, 39], prolonged cycles > 45 days (6 studies; 8.8%, 10%, 10%, 3%, 3.7%, 26%, on September 26, 2021 by guest. Protected copyright. 16% users) [20a, 20b, 21, 23, 36, 25 26 38, 39], scanty bleeding lasting 1 or 2 days (2 studies; 12%, 36.7% users) [36, 38], and menstrual delay > 30 days (1 study; 15 % users) [39]. 27 28 Five studies report continuous bleeding as a side effect. Of these, three are case reports of women on unsupervised long-term use of the pill, 29 30 presenting with continuous bleeding of 10 to 45 days duration [40, 41, 42]. Two other studies report continuous bleeding among 1% of 31 centchroman users [36, 38]. The Indian National guidelines on oral contraceptive use, report menstrual delay among 8% of centchroman users, 32 33 and state it typically occurs in the first three months of centchroman use [4]. 34 35 36 37 38 39 40 41 42 19 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 20 of 33
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3.5.2 Other side effects BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 The phase I trial on centchroman, initiated in 1970’s included 51 participants (23 6 7 females and 28 males) [17]. At the end of this phase, it was concluded that a dose of 8 5-320 mg centchroman is well tolerated by humans, because it did not show any 9 10 major side effect or any abnormality in laboratory parameters. 11 12 Phase III multicentric trials (till 1984) reported one women with 8 kg weight gain 13 14 over 34 months period of drug use, one of loose stools, vomiting and two with fever 15 [21]. In the phase III (till 1986) five women complained of giddiness, five of 16 17 headache, one of anorexia, one of loose motions and vomiting and one ectopic 18 For peer review only 19 pregnancy [20]. 20 21 The other side effects reported from included studies were: headache (2 studies; 1% 22 and 4% users) [37, 38], giddiness (2 studies; 1.3% and 12%) [37, 38], nausea (1 study, 23 24 0.7%) [38], and giddiness with abdominal pain (1 study; 8% at 3 months and 12% 25 26 users at 6 months) [39]. In addition, three case reports provide detail on women with 27 complaints of continuous bleeding and on investigation are found to be severely 28 29 anemic (Hb: 4 g/dl, 5 g/dl and 7 g/dl) [40, 41, 42]. Further, an observational study 30 31 reported anemia in 11% users [37]. 32 33 3.5.3 Changes in the ovaries and uterus 34 Seven studies [27, 34, 36, 38, 40, 41, 42] in the review report the ultrasound findings 35 36 among centchroman users (table 6). The main findings reported by these studies are: 37 http://bmjopen.bmj.com/ 38 (a) Three case reports found a bulky uterus with distorted endometrial cavity [40, 41, 39 40 42]. (b) One study found ovarian enlargement among 18% of the users [38]. In 41 another study among the 175 women who were followed up for 40 months on 42 43 centchroman, 15% showed ovarian enlargement. The enlargement was unilateral, 44 45 transient and never persisted and got resolved despite centchroman therapy [27]. One on September 26, 2021 by guest. Protected copyright. 46 study among 17 women, however, showed no changes in ovaries [36]. The 47 48 preliminary results of the phase IV trial report 4 women with ovarian cysts < 5 cms 49 50 and 2 women with cysts > 5 cms [34]. 51 Table 6: Summary of studies on ultrasound findings among centchroman users 52 53 Ref* No. of women Dosage of centchroman Duration of Ultrasound findings 54 who underwent Centchroman 55 USG intake 56 40 1 30 mg once a week 7 years Enlarged uterus with well 57 delineated endometrial thickness 58 & a mixed echogenic collection 59 in a distorted endometrial cavity 60 41 1 30 mg once a week 10 years Mixed echogenic collection in a
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(irregular and distorted endometrial cavity of a BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 unsupervised) bulky uterus (101 X 84 mm). 5 Ovaries were normal 6 38 28 (of 153 30 mg twice weekly for 3-12 months 20 women had normal looking 7 participants) 3 months, followed by ovaries, 8 30 mg weekly once 4 (14.2%) women had follicular 9 cysts 10 4 (14.2%) women had corpus 11 luteal cysts 12 No cyst was bigger than 2.5-3 13 cm 14 42 1 60 mg twice weekly for 2 years Bulky uterus with 8X4 cm hyper 15 3 months followed by echoic area with increased AV 16 once weekly channels within it. 17 (unsupervised use) Endometrium was not separately 18 For peer review only made out 19 36 17 30 mg twice weekly for 12 months No significant ovarian 20 3 months followed by 30 enlargement was detected during 21 mg once weekly centchroman use 22 23 64 (of 377 30 mg twice a week for 12-30 months Two cases of enlarged ovaries 23 participants) 3 months, followed by One showed enlarged ovary at 6 24 30 mg once a week months and one at 12 months 25 In both cases, enlargement was 26 due to mature unruptured 27 follicle 28 On subsequent examination at 29 12 and 20 months, ovaries were 30 normal. 31 27 175 30 mg twice a week for Upto 40 months 15% of women had ovarian 32 3 months, followed by enlargement 33 30 mg once a week Enlargement was unilateral and 34 transient 35 * The complete study titles are in the reference section. 36 37 No additional data is available. http://bmjopen.bmj.com/ 38 4. DISCUSSION 39 40 This is the first scoping review that systematically identified and summarized the 41 42 studies on centchroman, as a contraceptive pill. Our primary aim for this scoping 43 review was to collate the overall evidence available on the current state of knowledge 44 45 on mechanism of action, pharmacokinetics, side effects and effectiveness of on September 26, 2021 by guest. Protected copyright. 46 47 centchroman as a weekly and post-coital contraceptive pill. The methods used 48 49 throughout the different stages of the review were rigorous, transparent and the 50 process is documented in sufficient detail to replicate the research approach. In 51 52 addition, we interviewed a product manager from the pharmaceutical company that 53 54 manufactures centchroman in India to gain insight on sales and marketing of 55 56 centchroman. He said that currently centchroman is only marketed in India as a 57 weekly contraceptive pill, though in the past it has been sold as an emergency post- 58 59 coital pill and was also marketed in South America for a short period. On 60
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effectiveness, with perfect use the failure rate of centchroman was 1-2%, but with BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 typical use the failure rate increases to 6-7%. We here recognize the potential conflict 6 7 of interest, as the pharmaceutical manager may be biased in responses to boost his 8 company sales. 9 10 This scoping review identified 33 primary research papers, annual reports, theses and 11 12 national guidelines on centchroman, from India published between 1976 and 2019. 13 14 Only two studies in our review report the mechanism of action of centchroman in 15 women (sample size: 8,10) [16, 18]. 16 17 Eight studies report the effectiveness of centchroman as a weekly contraceptive pill 18 For peer review only 19 involving a total of 2544 women. The reported effectiveness ranged from 96% to 98% 20 21 in clinical trials and 93% to 100% in observational studies. This review thus suggests 22 that the effectiveness of centchroman as a weekly contraceptive is slightly lower than 23 24 what is noted as 98-99% in the Indian National guidelines [4]. Only one RCT among 25 26 150 women reports the effectiveness of Centchroman as a post-coital pill [35]. It was 27 98% effective when taken as a single 60 mg within 120 hours of unprotected 28 29 intercourse. The detailed results of phase IV trials would provide conclusive 30 31 information on effectiveness. 32 33 Thirteen studies report side effects of centchroman use as an oral contraceptive. 34 Continuous bleeding and prolonged cycles > 45 days were the two most commonly 35 36 reported side effects among centchroman users. The side effects profile is similar to 37 http://bmjopen.bmj.com/ 38 that seen with hormonal contraceptive pills. The studies on side effects are of low 39 40 quality with small sample size. The largest sample for observational studies was 153 41 women and maximum follow up was of 12 months. This limits meaningful 42 43 conclusions to be drawn. Though the phase IV drug trial included a large sample (934 44 45 users), but the detailed results of this phase are not published and were not available on September 26, 2021 by guest. Protected copyright. 46 on request hence could not be used in the review. To the best of our knowledge there 47 48 has been no published scientific trial comparing side effects of centchroman to other 49 50 safe and effective oral contraceptive pills. There is a need for studies with robust 51 52 study designs comparing centchroman with other hormonal methods. 53 The Indian National guidelines [4] have menstrual delay among 8% of the 54 55 centchroman users, and do not mention any other side effects. We suggest the 56 57 guidelines be updated to include other side effects as well, so that the health providers 58 can comprehensively counsel the women on the possible side effects during 59 60 counseling. 22
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5. CONCLUSIONS BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 Our scoping review provides a broad and a comprehensive review of currently 6 7 available literature on centchroman, when used as a contraceptive pill. The review 8 demonstrates that despite evidence on effectiveness of centchroman, more research is 9 10 needed on side effects and mechanism of action. Insufficient evidence exists on its 11 12 use as a post-coital contraceptive pill. Robust study designs are needed such as RCT 13 14 or longitudinal studies to compare effectiveness and safety of centchroman with other 15 short-term modern contraceptives such as combined hormonal oral pills (COCs) or 16 17 progesterone only pills (POPs) contraceptives. It is clear that there are extensive gaps 18 For peer review only 19 in the literature that warrant further studies, both in Indian and International settings. 20 21 The uncertainty and diversity of side effects and effectiveness in the studies across 22 India, implies lack of body of evidence to make global recommendations on 23 24 centchroman, a contraceptive method that is licensed and used in the second most 25 26 populous country in the world. 27 6. ETHICAL APPROVAL AND CONSENT TO PARTICIPATE 28 29 Not applicable 30 31 7. CONSENT FOR PUBLICATION 32 33 All authors read and approved the final manuscript. This review contains the 34 collective views of an international group of experts, and does not necessarily 35 36 represent the decisions or the stated policy of the World Health Organization. 37 http://bmjopen.bmj.com/ 38 8. COMPETING INTERESTS 39 40 The funding sources did not play a role in the study design, analysis and interpretation 41 of data, in the writing of the report, or in the decision to submit the article for 42 43 publication. The conclusions and opinions expressed here are those of the authors and 44 45 not necessarily those of the funder. on September 26, 2021 by guest. Protected copyright. 46 9. FUNDING 47 48 The UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, 49 50 Development and Research Training in Human Reproduction (HRP), a co-sponsored 51 52 program executed by the WHO, funded this work 53 10. AUTHOR’S CONTRIBUTIONS 54 55 The idea for this publication was conceived by RK and JK. RK and KPA prepared the 56 57 first draft. MA, CAJ, KM and JK provided significant contributions to the draft. All 58 authors reviewed the draft manuscript and approved the final manuscript for 59 60 publication. 23
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11. DATA AVAILABILITY BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 All data relevant to the study are included in the article or uploaded as supplementary 6 7 information 8 12. ACKNOWLEDGEMENTS 9 10 We would like to thank Mr. Tomas John Allen, librarian at WHO Geneva for his 11 12 assistance in developing a search strategy and running the search for this scoping 13 14 review. We would like to thank Drs. Manisha Malhotra, Bulbul Sood, Saswati das 15 (JHPIEGO), Shalini Singh (ICMR) for their support in identifying the stakeholders 16 17 and for their valuable suggestions on the protocol and the initial draft of this scoping 18 For peer review only 19 review. We would also like to thank all the stakeholders who participated in the 20 21 interviews and shared their experiences with centchroman use. 22 ABBREVIATIONS 23 24 CDRI-Central Drug Research Institute 25 26 Cmax- Peak serum concentration of Centchroman 27 Cmin- Steady state minimum concentration of centchroman 28 29 COCs- Combined hormonal oral pills 30 31 EMA- European Medicines Agency 32 33 FDA- Food and Drug Administration 34 HLL- Hindustan Latex Limited 35 36 ICMR-Indian Council of Medical Research 37 http://bmjopen.bmj.com/ 38 INN- International non-proprietary name 39 40 Kd- Dissociation rate constant 41 MF- Method Failure 42 43 MeSH- Medical Education Subject Headings 44 45 POPs- Progesterone only pills on September 26, 2021 by guest. Protected copyright. 46 RCT- Randomized control trial 47 48 SERM- Selective Estrogen Receptor Modulator 49 50 SRH- Sexual and reproductive health 51 52 UNFPA- United Nations Population Fund 53 USAID- United States Agency for International Development 54 55 USG- Ultrasonography 56 57 UF- User Failure 58 Vd- Volume of Distribution 59 60 WHO- World Health Organization 24
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REFERENCES: BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 1. Singh MM. Centchroman, a selective estrogen receptor modulator, as a 6 7 contraceptive and for the management of hormone-related clinical disorders. 8 Medicinal Research Reviews2001;21(4):302-347. 9 10 2. Population foundation of India. Spacing methods of family planning. Available 11 12 from http://populationfoundation.in/files/fileattached/Fileattached-1492415902- 13 th 14 Family_Planning_methods_Eng.pdf. Cited 17 November 2017 15 3. Kamboj V, Ray S, Anand N. Centchroman: A safe reversible post-coital 16 17 contraceptive with curative and prophylactic activity in many disorders. Frontiers 18 For peer review only 19 in Bioscience(Elite edition)2018;10:1-14 20 21 4. Family planning division, Ministry of Health and Family welfare, Government of 22 India. Reference manual for Oral contraceptive pills. New Delhi: Ministry of 23 24 Health and Family welfare -Government of India; 2016. 25 26 5. D. Balasubramanian. On conception and contraception: The story of Saheli; The 27 Hindu: 24th June 2017. Available from https://www.thehindu.com/sci- 28 29 tech/science/on-conception-and-contraception-the-story-of- 30 31 saheli/article19140909.ece. Cited 28th June 2018. 32 33 6. Lal J. Clinical pharmacokinetics and interaction of centchroman - A mini review. 34 Contraception2010;81(4):275-280. 35 36 7. World Health Organization. WHO drug information: Recommended INN list 34 37 http://bmjopen.bmj.com/ 38 international nonproprietary names for pharmaceutical substances. Volume 8, 39 40 Number 4. Geneva: World Health Organization; 1994. 41 8. Chawla PC. CSIR’s novel contraceptive drug- a woman’s true Saheli. In: Chawla 42 43 PC, editor. CSIR News: Progress, promise and prospects. New Delhi: NISCAR 44 45 Press; 2010,Volume 60(No. 15 & 16):171-172. on September 26, 2021 by guest. Protected copyright. 46 9. Population Research Institute. News from Latin America. One less weapon 47 48 against the unborn: The abortion pill gets pulled from market. January 1 2010. 49 50 Population Research Institute. Available from https://www.pop.org/news-from- 51 52 latin-america-one-less-weapon-against-the-unborn-the-abortion-pill-gets-pulled- 53 from-the-market/. Cited 23rd November 2017 54 55 10. HLL Lifecare Limited. Innovating for healthy generations. Annual report 2013- 56 57 2014. Available from 58 http://www.lifecarehll.com/page/render/reference/Annual_Report. Cited 20th 59 60 October 2017 25
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regulation and reproduction, Eds: CP Puri, PFA VanLook New Delhi, Wiley BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 Eastern Ltd.1994:61-68 6 7 24. Paliwal JK, Grover PK, et al. Excretion of centchroman in breast milk. British 8 Journal of Clinical Pharmacology1994;38(5):485-486. 9 10 25. Gupta RC, Paliwal JK, Nityanand S, et al. Centchroman: A new non-steroidal oral 11 12 contraceptive in human milk. Contraception1995;52(5):301-305. 13 14 26. Lal J, Asthana OP, Nityanand S, et al. Pharmacokinetics of centchroman in 15 healthy female subjects after oral administration. Contraception1995;52(5):297- 16 17 300. 18 For peer review only 19 27. Nityanand S, Gupta RC, Kamboj VP, et al. Centchroman: current status as a 20 21 contraceptive. Indian progress in family welfare: clinical research on maternal and 22 child health & contraception, Eds: SC dawn, A Misra Calcutta, Dawn 23 24 books1995:26-31. 25 26 28. Gupta RC, Nityanand S, Asthana OP, et al. Pharmacokinetics of centchroman in 27 nursing women and passage into breast milk. Clinical Drug 28 29 Investigation1996;11(5):305-309. 30 31 29. Lal J, Nityanand S, Asthana OP, et al. Comparative bioavailability of two 32 33 commercial centchroman tablets in healthy female subjects. Indian Journal of 34 Pharmacology1996;28(1):32-34. 35 36 30. Khurana M, Paliwal JK, Kamboj VP, et al. Binding of centchroman with human 37 http://bmjopen.bmj.com/ 38 serum as determined by charcoal adsorption method. International Journal of 39 40 Pharmaceutics1999;192(2):109-114. 41 31. Lal J, Nityanand S, Asthana OP, et al. Optimization of contraceptive dosage 42 43 regimen of Centchroman. Contraception2001;63(1):47-51. 44 45 32. Khurana M, Lal J, Kamboj M, et al. Uptake of centchroman by the human uterus. on September 26, 2021 by guest. Protected copyright. 46 Clinical Drug Investigation2002;22(10):715-718. 47 48 33. Indian Council of Medical Research (ICMR). Reproductive Health: Annual report 49 50 2009-10. Available from http://www.icmr.nic.in/annual/2009-10/english/rh.pdf. 51 th 52 Cited 20 November 2017 53 34. Indian Council of Medical Research (ICMR). Reproductive Health: Annual report 54 55 2010-11. Available from http://www.icmr.nic.in/annual/2010- 56 th 57 11/English%20Annual%20Report/rh.pdf. Cited 20 November 2017 58 59 60
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35. Mittal S, Sehgal R, Jindal VI, et al. Single dose levonorgestrel and two regimens BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 of centchroman for emergency contraception. Journal of the Turkish German 6 7 Gynecology Association2008;9(3):132-137. 8 36. Tandon D. Effect of centchroman on biochemical profile, ovulation and ovarian 9 10 size. Masters of Surgery Thesis. Bundelkhand University. 1992. Available from 11 12 https://ia601601.us.archive.org/16/items/in.ernet.dli.2015.269787/2015.269787.Ef 13 14 fect-Of.pdf 15 37. Ghosh S. Prospective observational study of the pattern of usage of oral 16 17 contraceptive pills. Masters of Pharmacy thesis. 2014. Available from 18 For peer review only 19 http://jadunivdspace.jdvu.ac.in/bitstream/123456789/29440/1/Acc.%20No.%20D 20 21 C%201823.pdf 22 38. Nair HS, Jayasimhan P. A prospective study of centchroman users with special 23 24 reference to its contraceptive benefit. Journal of evidence based medicine and 25 26 healthcare2016;3(98):5374-5380. 27 39. Agrawal P, Kushwa V, Mangal BK. Evaluation of safety profile of centchroman 28 29 for contraceptive purpose. National journal of medical and allied 30 31 sciences2016;5(2):41-44. 32 33 40. Malhotra KP, Sherpa M, Bhatia A. Centchroman: Is unsupervised long-term use 34 warranted? Case report. European Journal of Contraception and Reproductive 35 36 Health Care2011;16(5):403-406. 37 http://bmjopen.bmj.com/ 38 41. Agarwal R., Radhakrishnan G, Radhika AG, et al. Abnormal uterine bleed- an 39 40 adverse event of long-term centchroman use? Indian journal of maternal and 41 child health2014;16(2):1-7. 42 43 42. Padmaja A, Vemulapalli P, Jaya Prada Devi K. Rare case of endometrial 44 45 hyperplasia following unsupervised prolonged use of ormeloxifene. IOSR Journal on September 26, 2021 by guest. Protected copyright. 46 of dental and medical sciences2013;5(4):55-57 47 48 43. Family planning division, Ministry of Health and Family welfare, Government of 49 50 India. An update on new family planning methods for ASHA. New Delhi: 51 52 Ministry of Health and Family welfare -Government of India; 2017. 53 44. Ministry of Health and family welfare, Government of India, United Nations 54 55 Population Fund. Contraceptive updates. Reference manual for doctors. New 56 57 Delhi: Ministry of Health and Family welfare; 2005. 58 59 60
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45. Central drug research institute, Lucknow. Annual report 2016-17. Available from BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 http://www.cdri.res.in/Annual_Reports/Annual_Report_2016_17.pdf. Cited 21st 6 7 October 2017 8 9 10 11 12 13 14 15 16 17 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
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 Key milestones on evolution of centchroman 20 21 22 23 24 25 26 27 28 29 30 31 32 33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40 41 on September 26, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 31 of 33 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 http://bmjopen.bmj.com/ 34 35 Prisma flow chart 36 37 38 39 40 41 on September 26, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 32 of 33 BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from
1 2 3 Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for 4 Scoping Reviews (PRISMA-ScR) Checklist 5 6 REPORTED SECTION ITEM PRISMA-ScR CHECKLIST ITEM 7 ON PAGE # 8 TITLE 9 Title 1 Identify the report as a scoping review. 1 10 ABSTRACT 11 Provide a structured summary that includes (as 12 applicable): background, objectives, eligibility criteria, Structured 13 2 sources of evidence, charting methods, results, and 2-3 summary 14 conclusions that relate to the review questions and 15 objectives. 16 INTRODUCTION For peer review only 17 Describe the rationale for the review in the context of what is already known. Explain why the review 18 Rationale 3 4-5 19 questions/objectives lend themselves to a scoping 20 review approach. 21 Provide an explicit statement of the questions and 22 objectives being addressed with reference to their key 23 Objectives 4 elements (e.g., population or participants, concepts, and 5 24 context) or other relevant key elements used to 25 conceptualize the review questions and/or objectives. 26 METHODS 27 Indicate whether a review protocol exists; state if and Protocol and where it can be accessed (e.g., a Web address); and if 28 5 - 29 registration available, provide registration information, including the registration number. 30 Specify characteristics of the sources of evidence used 31 Eligibility criteria 6 as eligibility criteria (e.g., years considered, language, 7 32
and publication status), and provide a rationale. http://bmjopen.bmj.com/ 33 Describe all information sources in the search (e.g., 34 Information databases with dates of coverage and contact with 7 6 35 sources* authors to identify additional sources), as well as the 36 date the most recent search was executed. 37 Present the full electronic search strategy for at least 1 38 Search 8 database, including any limits used, such that it could be 6 39 repeated. 40
Selection of on September 26, 2021 by guest. Protected copyright. State the process for selecting sources of evidence (i.e., 41 sources of 9 7 screening and eligibility) included in the scoping review. 42 evidence† 43 Describe the methods of charting data from the included 44 sources of evidence (e.g., calibrated forms or forms that 45 Data charting have been tested by the team before their use, and 10 8 46 process‡ whether data charting was done independently or in 47 duplicate) and any processes for obtaining and 48 confirming data from investigators. 49 List and define all variables for which data were sought Data items 11 8 50 and any assumptions and simplifications made. If done, provide a rationale for conducting a critical 51 Critical appraisal of appraisal of included sources of evidence; describe the 52 individual sources 12 - methods used and how this information was used in any 53 of evidence§ 54 data synthesis (if appropriate). Describe the methods of handling and summarizing the 55 Synthesis of results 13 8 56 data that were charted. 57 58 59 1 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 33 of 33 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from
1 2 3 REPORTED SECTION ITEM PRISMA-ScR CHECKLIST ITEM 4 ON PAGE # 5 RESULTS 6 Give numbers of sources of evidence screened, Selection of 7 assessed for eligibility, and included in the review, with sources of 14 8 8 reasons for exclusions at each stage, ideally using a flow evidence 9 diagram. 10 Characteristics of For each source of evidence, present characteristics for 11 sources of 15 9-11 which data were charted and provide the citations. 12 evidence 13 Critical appraisal If done, present data on critical appraisal of included within sources of 16 - 14 sources of evidence (see item 12). 15 evidence 16 Results of For peerFor each included review source of evidence, only present the 17 individual sources 17 relevant data that were charted that relate to the review 11-21 18 of evidence questions and objectives. Summarize and/or present the charting results as they 19 Synthesis of results 18 11-21 20 relate to the review questions and objectives. 21 DISCUSSION 22 Summarize the main results (including an overview of Summary of concepts, themes, and types of evidence available), link 23 19 21-22 24 evidence to the review questions and objectives, and consider the 25 relevance to key groups. 26 Limitations 20 Discuss the limitations of the scoping review process. 23 27 Provide a general interpretation of the results with 28 Conclusions 21 respect to the review questions and objectives, as well 23 as potential implications and/or next steps. 29 FUNDING 30 Describe sources of funding for the included sources of 31 evidence, as well as sources of funding for the scoping 32 Funding 22 24 review. Describe the role of the funders of the scoping http://bmjopen.bmj.com/ 33 review. 34 JBI = Joanna Briggs Institute; PRISMA-ScR = Preferred Reporting Items for Systematic reviews and Meta-Analyses 35 extension for Scoping Reviews. 36 * Where sources of evidence (see second footnote) are compiled from, such as bibliographic databases, social media 37 platforms, and Web sites. 38 † A more inclusive/heterogeneous term used to account for the different types of evidence or data sources (e.g., 39 quantitative and/or qualitative research, expert opinion, and policy documents) that may be eligible in a scoping review as opposed to only studies. This is not to be confused with information sources (see first footnote). 40
‡ The frameworks by Arksey and O’Malley (6) and Levac and colleagues (7) and the JBI guidance (4, 5) refer to the on September 26, 2021 by guest. Protected copyright. 41 process of data extraction in a scoping review as data charting. 42 § The process of systematically examining research evidence to assess its validity, results, and relevance before 43 using it to inform a decision. This term is used for items 12 and 19 instead of "risk of bias" (which is more applicable 44 to systematic reviews of interventions) to include and acknowledge the various sources of evidence that may be used 45 in a scoping review (e.g., quantitative and/or qualitative research, expert opinion, and policy document). 46 47 48 From: Tricco AC, Lillie E, Zarin W, O'Brien KK, Colquhoun H, Levac D, et al. PRISMA Extension for Scoping Reviews (PRISMA- 49 ScR): Checklist and Explanation. Ann Intern Med. ;169:467–473. doi: 10.7326/M18-0850 50 51 52 53 54 55 56 57 58 59 2 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 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.R2
Article Type: Original research
Date Submitted by the 27-Aug-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
Primary Subject http://bmjopen.bmj.com/ Reproductive medicine Heading:
Secondary Subject Heading: Obstetrics and gynaecology
Keywords: centchroman, safety, effectiveness, oral pill, contraception, ormeloxifene
on September 26, 2021 by guest. Protected copyright.
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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
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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. 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. Two studies 30 31 reported mechanism of action of centchroman. Pharmacokinetics was reported by five 32 33 studies among non-breast feeding women and four studies among breast-feeding 34 women. Eight studies reported on effectiveness ranging between 93-100%. 35 36 Pregnancies due to user failure ranged from 2.6 % to 10.2 %. Although side effects 37 http://bmjopen.bmj.com/ 38 were reported in thirteen studies, but the incidence varied greatly between the studies. 39 40 Continuous bleeding and prolonged cycles > 45 days were the most commonly 41 reported side effects. All studies conducted had a small sample size and the duration 42 43 of follow up of women was 12 months or less. Fifty five percent of studies were by 44 45 the developers of the pill (CDRI) and results of the phase IV clinical trial were on September 26, 2021 by guest. Protected copyright. 46 unavailable. 47 48 Conclusions 49 50 The scoping review shows that studies with robust designs and conducted in 51 52 international context are lacking. Insufficient evidence exists on centchroman use as a 53 post-coital contraceptive pill. The broad uncertainty in range of side effects and 54 55 effectiveness in the studies implies insufficient evidence to make global 56 57 recommendations on centchroman that is currently licensed as a contraceptive in 58 India. 59 60 KEYWORDS: Centchroman, safety, effectiveness, oral pill, contraception, 2
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Ormeloxifene. BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 Strengths and Limitations of this study 6 7 Strength of our study is that it is the first scoping review to explore the 8 mechanism of action, pharmacokinetics, effectiveness and side effects of 9 10 centchroman, when used as a weekly or post-coital contraceptive pill. 11 12 A limitation of our review is that we are likely to have missed studies on 13 14 mechanism of action of centchroman since animal studies were excluded from 15 the review. 16 17 All identified studies in this scoping review were from India. Additionally, 18 For peer review only 19 roughly half of the studies in this review were published from the developers 20 21 of the drug (CDRI). 22 There is no detailed drug trial on use of centchroman as a post-coital 23 24 contraceptive pill. 25 26 Studies on side effects of centchroman as a contraceptive pill are limited by 27 28 small sample size, short duration of follow-up and the fact that all studies have 29 been conducted in India. 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
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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 [3, 5] Centchroman (3, 4 trans-2, 2-dimethyl-3- 28 29 phenyl 4-p (β- pyrrolidinoethoxy) phenyl 7-methoxychroman) in 1967 [3, 6]. Since it 30 31 was made at CDRI and belongs to the chroman family, it was named as Centchroman. 32 33 In 1994, centchroman was given an International non-proprietary name (INN) as 34 Ormeloxifene [7]. Following pre-clinical and clinical studies (phase 1 and 2) in 1989 35 36 the Drug Controller General of India approved centchroman as an oral contraceptive 37 http://bmjopen.bmj.com/ 38 pill in 1991 [3, 6]. It was available in the Indian market since 1992. It was first 39 40 manufactured by Torrent pharmaceuticals, Ahmedabad and marketed under brand 41 name of Centron. Later Hindustan Latex Limited (HLL) Life care Limited; 42 43 Thiruvananthapuram manufactured it under the brand names Choice-7 and Saheli [8]. 44 45 The Ministry of Health and family welfare, India has distributed centchroman at a on September 26, 2021 by guest. Protected copyright. 46 subsidized cost since 1995 (social marketing scheme) [3, 6]. 47 48 In 2008, HLL Lifecare entered the international market by launching centchroman as 49 50 a post-coital pill under the brand name Ivyfemme in Peru, South America [9]. 51 52 However, in 2010 the license to sell the pill was revoked by Peru’s Directorate 53 General of supplies and drugs. The reason given for this was that the pill acted by 54 55 preventing implantation of a fertilized egg and sale of any abortifacient drug was 56 57 considered illegal in Peru [9]. In 2013, HLL Lifecare launched centchroman as a post- 58 coital pill in India under the brand name Tatkal-72 [10]. The production of Tatkal-72 59 60 was discontinued in 2014 due to restrictions on marketing and advertising of 4
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emergency contraceptive pills in India. BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 The Ministry of Health and family welfare, India in April 2016 decided to expand oral 6 7 contraceptive options by including centchroman in the National family planning 8 program under the brand name Chhaya [4, 5, 11]. Chhaya is available to women 9 10 through the public delivery system free of cost. Oral contraceptives that are safe 11 12 among breastfeeding women have a better potential to improve the use of family 13 14 planning methods by postpartum women, hence centchroman was included in the 15 National family planning program. Figure 1 depicts the key milestones in the 16 17 evolution of centchroman in India. 18 For peer review only 19 Figure 1: Key milestones on evolution of centchroman 20 21 In this review we have focused on the use of centchroman as an oral contraceptive pill 22 (weekly pill and post-coital pill). As a weekly contraceptive pill, the recommended 23 24 dosage of centchroman is a 30 mg pill twice a week for twelve weeks followed by a 25 26 30 mg pill once a week [4, 5]. Centchroman as an emergency post-coital pill is taken 27 as a 60 mg dose within 72 hours of intercourse [12]. 28 29 We are conducting this scoping review to determine the scope/ coverage of the body 30 31 of literature on effectiveness, safety, pharmacokinetics and mechanism of action of 32 33 centchroman as a contraceptive pill (weekly and post-coital). This review will identify 34 and map the types of available evidence on centchroman as a contraceptive pill and 35 36 determine any knowledge gaps 37 http://bmjopen.bmj.com/ 38 1.1 Aim & Objectives 39 This scoping review aims to systematically include the entire range of published and 40 41 grey literature on: 42 43 Extent and type of evidence on effectiveness and side effects of using 44 45 centchroman as a contraceptive pill (weekly and post-coital pill). on September 26, 2021 by guest. Protected copyright. 46 47 Extent of evidence on mechanism of action of centchroman when used as a 48 contraceptive in women. 49 50 Extent of evidence on pharmacokinetics of centchroman among both non- 51 52 lactating and breastfeeding women. 53 54 55 2. METHODS 56 57 A protocol for this scoping review was developed a priori using the Arksey and 58 59 O’Malley York’s five-stage framework [13]. The 5 steps of the scoping review were: 60
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(1) identifying the research question; (2) identifying the search strategy; (3) study BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 selection; (4) data charting; and (5) collating, summarizing and reporting the results. 6 7 Step 1: Identification of the research question 8 This scoping review was conducted to answer the following primary research 9 10 question: What is the current state of evidence on effectiveness and side effects of 11 12 centchroman as a contraceptive pill (weekly pill and post-coital pill)? The secondary 13 14 research questions were: What is current available evidence on mechanism of action 15 of centchroman in women? What is current evidence on pharmacokinetics of 16 17 centchroman in breastfeeding women and non-lactating women? 18 For peer review only 19 Step 2: Identification of relevant studies (Search strategy) 20 21 To address the research questions, we developed a detailed search strategy to identify 22 all relevant publications on centchroman. The following MeSH (Medical Education 23 24 Subject Headings) terms were identified and used: centchroman, ormeloxifene, saheli, 25 26 safety, pharmacokinetics, effectiveness, efficacy, and mechanism of action. Using the 27 search terms, we systematically searched the following electronic databases: 28 29 MEDLINE, EMBASE, INDMED, Cochrane library, and Google scholar for studies 30 31 published between 1970 up to 27th July 2017. The search was most recently re-run on 32 rd 33 23 January 2019 (no new studies added). 34 No limits were placed on the searches. An example of the search strategy in Embase 35 36 is given below: “ 'centchroman'/exp OR '1 [2 [4 (7 methoxy 2, 2 dimethyl 3 37 http://bmjopen.bmj.com/ 38 phenylchroman 4 yl) phenoxy] ethyl] pyrrolidine':ti,ab,de OR '2, 2 dimethyl 3 phenyl 39 40 4 [4 (2 pyrrolidinoethoxy) phenyl] 7 methoxychroman':ti,ab,de OR '3, 4 trans 2, 2 41 dimethyl 3 phenyl 4 [4 (2 pyrrolidinoethoxy) phenyl] 7 methoxychroman':ti,ab,de OR 42 43 '7 methoxy 2, 2 dimethyl 3 phenyl 4 [4 (2 pyrrolidin 1 ylethoxy) phenyl] 44 45 chroman':ti,ab,de OR 'centron':ti,ab,de OR 'choice 7':ti,ab,de OR on September 26, 2021 by guest. Protected copyright. 46 'levormeloxifene':ti,ab,de OR 'ormeloxifene':ti,ab,de OR 'saheh':ti,ab,de OR 47 48 'saheli':ti,ab,de OR 'shaeli':ti,ab,de OR 'trans 2, 2 dimethyl 3 phenyl 4 [4 (2 49 50 pyrrolidinoethoxy) phenyl] 7 methoxychroman':ti,ab,de OR ‘centchroman’:ti,ab,de 51 52 OR ‘31477-60-8’:rn”. 53 Furthermore, websites such as CDRI (Central Drug Research Institute), ICMR (Indian 54 55 Council of Medical Research), clinical trial registry of India, WHO, and Popline were 56 57 searched for studies and scientific reports on centchroman. We searched websites of 58 two major drug authorities: FDA (Food and Drug Administration) and EMA 59 60 (European Medicines Agency) and found no information on the relationship of 6
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ormeloxifene/ centchroman and oral contraceptive were available on these websites. BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 In addition, we searched for conference proceedings, and student master’s and PhD 6 7 thesis. The reference lists of all the retrieved studies were searched to identify any 8 additional studies of relevance. We contacted authors to provide studies and 9 10 additional information that was unavailable. 11 12 Step 3: Selection of studies for review 13 14 We included studies from 1970 to present (2019), to reflect the period during which 15 centchroman was first synthesized and drug trials initiated. No limits were placed on 16 17 language and location of study. We included studies on women using centchroman 18 For peer review only 19 only as a contraceptive pill (weekly pill or emergency post-coital pill). Table 1 depicts 20 21 the eligibility criteria. 22 Table 1: Inclusion/ exclusion criteria 23 24 Criteria Inclusion Exclusion 25 Study design Quantitative, qualitative and mixed Studies on animals, narrative review 26 methods study, systematic review 27 Location Any country None 28 Date 1970- Present (2019) Before 1970 29 Language All languages None 30 Research focus Main focus on safety, side effects, Main focus on non-contraceptive uses 31 effectiveness, mechanism of action and of centchroman 32 pharmacokinetics, when used as a 33 contraceptive 34 Document type Case reports, scientific reports, primary Narrative reviews, newspaper and 35 research article, systematic reviews, magazine articles. 36 commentaries, letter to editors, 37 conference proceedings, Masters and http://bmjopen.bmj.com/ PhD thesis 38 39 40 After running the search, all the retrieved studies were exported into EndNote X7 41 42 reference management software. The EndNote program was used to check for 43 44 duplication. The study selection process consisted of two levels of screening: 45 on September 26, 2021 by guest. Protected copyright. 46 (1) Title and abstract review: Two reviewers (RK, KPA) independently screened the 47 title and abstract of all the retrieved citations for inclusion guided by the eligibility 48 49 criteria. An article that was considered relevant by either or both the reviewers were 50 51 included for full text review, and any discrepancies were resolved through discussion. 52 Full text articles that were excluded at the screening stage had reasons for exclusions 53 54 documented. 55 56 (2) Full text review: In the second step, the reviewers (RK, KPA) independently 57 58 assessed the full text articles to determine if they met the inclusion and exclusion 59 criteria. Any disagreement was resolved by mutual discussions between the reviewers. 60
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For included studies, two authors (RK, KPA) extracted the data using the data- BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 charting sheet. 6 7 Step 4: Charting the Data 8 A data-charting sheet was designed in Microsoft Excel to extract the general 9 10 characteristics of each study. Information retrieved included study characteristics 11 12 (authors, country, region, year published, study aim, study design, number of 13 14 participants), key research topic (side effects, effectiveness, mechanism of action or 15 pharmacokinetics of centchroman). For each research topic separate data charting 16 17 sheets were used to extract relevant information from each included study. The data 18 For peer review only 19 charting sheets were constantly updated through the review process. 20 21 Step 5: Collating, summarizing and reporting the results 22 To summarize the findings for this scoping review, each author repeatedly reviewed 23 24 the extracted evidence independently. The extracted data was summarized based on 25 26 the individual research questions and around the following outcomes: effectiveness 27 and side effects when used as a weekly or post-coital contraceptive pill, and 28 29 mechanism of action as contraceptive pill in women and pharmacokinetics of 30 31 centchroman in non-lactating women and in breast-feeding women. The data 32 33 extracted in the data-charting sheet was analyzed descriptively (frequencies and 34 percentages) to facilitate categorization, charting and discussion. Scoping reviews 35 36 aimed to identify, map findings and to provide an overview of the available literature 37 http://bmjopen.bmj.com/ 38 in the topic area rather than an assessment of study quality [14]. 39 40 Patient and Public Involvement: Patients and public were not involved in this review. 41 3. RESULTS 42 43 Of the 664 articles initially identified by our search criteria, only 33 met the inclusion 44 45 criteria for this scoping review (figure 2). Of these 33 studies, twenty-one (64%) were on September 26, 2021 by guest. Protected copyright. 46 experimental (20 non-randomized clinical trials and 1 randomized controlled trial), 47 48 four (12%) were observational (descriptive studies), three (9%) were case reports, 49 50 three (9%) were National guidelines and two (6%) were annual reports. 51 Figure 2: Prisma flow chart 52 53 54 We identified 8 studies on effectiveness of centchroman as a weekly contraceptive 55 56 pill, 1 study on effectiveness of centchroman as a post-coital pill, 13 studies on side 57 58 effects of centchroman (weekly and post-coital pill), 2 on mechanism of action in 59 60
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women and 12 studies on pharmacokinetics among non-lactating and breast-feeding BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 women. 6 7 All studies were conducted in India and reported in English. The earliest study was 8 published in 1976 and the latest in 2017. The full texts of studies were available for 9 10 all except one study for which only the abstract was available [15]. Research 11 12 publications on centchroman have increased in frequency in the recent years with 13 14 39.4% of studies published in the last 10 years (2007 – 2017) and 60.6% in the 15 previous 30-year period (1976-2006). Roughly half (54.5%) of the studies were 16 17 published from the developers of the pill (CDRI), and all were clinical trials. The 18 For peer review only 19 general characteristics of the included studies are detailed in table 2. 20 21 22 Table 2: General characteristics of included studies 23 S.no Study Author/ Year Sample Purpose Outcome 24 design size
25 1. Roy S. et al* 8 To study the ovulation inducing action of Mechanism of 26 (1976) [16] centchroman in anovulatory women action 27 2. Chandra H. a) 40 To determine the maximum tolerated dose of Side effects et* al (1977) b) 28 centchroman in human volunteers and to find out 28 [17] any toxic effects the study was carried out in 2 29 parts a) single dose study b) multiple dose study 30 3. Vaidya R. et 10 To evaluate various clinical and hormonal Mechanism of 31 al* (1977) parameters during immediate pre-therapy and the action, Side effects 32 [18] first therapy cycle for evaluating its effect on 33 hypothalamic-pituitary-ovarian axis 4. Srivastava - To study the binding of centchroman to steroid Pharmacokinetics 34 A.K. et al* binding proteins in human plasma 35 (1984) [19] 36 5. Nityanand S. a) Till To determine the contraceptive efficacy of Effectiveness 37 et al* (1988) Nov centchroman in a multicentric trial of (weekly), Side http://bmjopen.bmj.com/ 38 [20] 1986 centchroman with 30 mg weekly dose. The study effects 39 - 648 reports results in two parts: a) Phase III clinical 40 April trial till November 1986 b) extended phase III 1987- Nov trials (April 1987- November 1988) 41 1988- 100 42 6. Puri V. et al* 467 To determine the contraceptive efficacy of Effectiveness 43 (1988)[21] centchroman in a multicentric trial in a 30 mg (weekly), Side 44 weekly dose. This paper reports results upto June effects 45 1984 on September 26, 2021 by guest. Protected copyright. 46 7. Paliwal J.K. 2 To determine pharmacokinetics after a 60 mg oral Pharmacokinetics 47 et* al (1989) dose of centchroman in normal healthy women [22] 48 8. Nityanand S. 377 a) To study the efficacy of centchroman in a Effectiveness 49 et al* (1994) biweekly cum weekly mode of administration; b) (weekly), Side 50 [23] To establish the safety of this dosage schedule by effects 51 serial ultrasounds. 52 9. Paliwal J.K. et 3 To determine pharmacokinetics of centchroman Pharmacokinetics 53 al* (1994) in serum and breast milk among three nursing 54 [24] women 10. Gupta R.C. et 13 To assess peak and trough levels of centchroman Pharmacokinetics 55 al* (1995) in breast milk and serum after a single 30 mg 56 [25] dose and after a 30 mg twice a week dose for 12 57 weeks and to calculate quantity ingested by 58 infants 59 11. trials Clinical Lal J. et al* 11 To determine pharmacokinetics of centchroman Pharmacokinetics 60 (1995) [26] after a single 30 mg dose in healthy women
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1 2 3 12. Nityanand S. a) 277 a) To study the effect of centchroman on ovaries, Pharmacokinetics BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 et al* (1995) b) 57 b) to determine reversibility and effect on 5 [27] 3 progeny among centchroman users, c) to study 6 whether it is safe to administer centchroman to 7 lactating women 13. Gupta R.C. et 4 To assess pharmacokinetics of centchroman in Pharmacokinetics 8 al* (1996) maternal serum & breast milk in nursing women 9 [28] after a single 30 mg tablet of centchroman 10 14. Lal J. et al* 6 To compare the bioavailability of two Pharmacokinetics 11 (1996) [29] pharmaceutically equivalent brands of 12 centchroman tablets: Saheli vs. Centron (double 13 blind-cross over study) 14 15. Lal J. et al* 3 To study the pharmacokinetic profile following Pharmacokinetics (1998) [15] the recommended dosage profile in normal 15 healthy women 16 16. Khurana M. et 2 To determine the extent of protein binding of Pharmacokinetics 17 al* (1999) centchroman at 1 and 10 /ml concentration in 18 [30] For peerdrug freereview human serum samples only 19 17. Lal J. et al* 60 To assess the pharmacokinetic parameters of Pharmacokinetics 20 (2001) [31] centchroman with dosing schedule of single 60 21 mg loading dose followed by 30 mg weekly doses. To assess steady state minimum 22 concentration of centchroman after 6 different 30 23 mg dosing schedules 24 18. Khurana M. et 17 To evaluate the tissue/ serum ratio of Pharmacokinetics 25 al* (2002) centchroman in uterus at the maximum drug 26 [32] concentration 27 19. ICMR (2009- 720 (439 Phase IV multicentric study to evaluate the Effectiveness 28 10) [33] centchrom efficacy and side effects of centchroman (weekly) an and 29 381 for 30 Cu-T) 31 20. ICMR (2010- 2087 Update of the phase IV multicentric study on Effectiveness 32 11) [34] (934 with centchroman (weekly) 33 centchrom 34 an and 1153 with 35 Cu-T) 36 21. Mittal S. et al 150 To investigate the use of centchroman as an Effectiveness (post- 37 (2008) [35] effective method of emergency contraception and coital pill), Side http://bmjopen.bmj.com/
38 RCT to compare its efficacy and side effects with effects 39 single and double dose of levonorgestrel regimen 40 22. Tandon D. 17 To study the effect of centchroman on Effectiveness 41 (1992) [36] biochemical profile, ovulation and ovarian size (weekly), Side (duration-12 months) effects 42 23. Ghosh S. 27 To assess the pattern of usage of oral Effectiveness 43 (2014) [37] contraceptive pills in a hospital setting (duration- (weekly), Side 44 8 months) effects 45 24. Nair H.S. et al 153 To study the effectiveness of centchroman as Effectiveness on September 26, 2021 by guest. Protected copyright. 46 (2016) [38] contraceptive, to study possible causes of (weekly), Side 47 centchroman failure, and to study incidence of effects 48 Descriptive study side effects of centchroman (duration- 12 months) 25. Agrawal P. et 25 To study the adverse drug reactions of Side effects 49 al (2016) [39] centchroman used for contraceptive purpose 50 (duration-12 months) 51 26. Malhotra K.P. 1 Case of young women using centchroman for a Side effects 52 et al (2011) long duration in an unsupervised fashion, 53 [40] presenting with menorrhagia 54 27. Agarwal R. et 1 Case of a women using centchroman for 10 years Side effects 55 al (2014) [41] in an unsupervised manner, presenting with abnormal uterine bleeding and enlarged uterus. 56 28. Padmaja A. et 1 Case of an unmarried 18 year women on Side effects 57
Case report al (2013) [42] unsupervised 60 mg centchroman twice weekly 58 (for menorrhagia) for 2 years, presents with c/o 59 excess menstrual flow 60
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1 2 3 29. MoH& FW, - Reference manual for oral contraceptive pills Dosage schedule, BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 Government side effects 5 of India 6 (2016) [4] 7 30. MoH& FW, - Guidelines on contraceptives: An update on new Dosage schedule, Government family planning methods for ASHA workers benefits and side 8 of India effects 9 (2017)[43] 10 31. manual MoH & FW, - Contraceptive updates-reference manual for Mechanism of 11 Government doctors on doses, advantages and side effects. action, side effects 12 of India The Government of India has planned to organize 13 (2005)[44] series of ‘contraception updates’ seminars for 14 Reference National Guideline/ doctors in public and private health care sector, to help standardize delivery of information. 15 32. Population - Report on spacing methods for family planning Mechanism of 16 foundation of action, 17 India (2014) effectiveness, side 18 [2] For peer review only effects and 19 advantages 20 33. CSIR-Central - Annual report of CSIR, which includes unique Unique features 21 drug research features of centchroman and details of its and details of its
Annual Report institute inclusion in the National family planning inclusion in 22 (2017) [45] program, India National FP 23 program 24 3.1 MECHANISM OF ACTION OF CENTCHROMAN 25 26 Two clinical trials in our review report the mechanism of action of centchroman 27 28 among women [16, 18]. The first study was conducted among 8 women with 29 ovulatory failure. The women were non-randomly allocated into one of three- 30 31 treatment arms, where centchroman was administered in doses of 15, 30 or 60 mg 32 33 daily for 10 to 20 days [16]. Increase levels of plasma progesterone, urinary 34 35 pregnanediol and estrogen were observed reflecting that centchroman stimulates the 36
pituitary ovarian axis. The authors concluded that centchroman could induce http://bmjopen.bmj.com/ 37 38 ovulation in anovulatory women. The second study was conducted among 10 healthy 39 40 women, non-randomly allocated into 2 groups. Six women received 120 mg/week and 41 four women received 60 mg/week schedule for two months. Increase in cycle length 42 43 was noticed in all cases probably due to lengthening of the follicular phase. The 44 45 authors concluded that centchroman at the mentioned doses does not seem to inhibit on September 26, 2021 by guest. Protected copyright. 46 47 ovulation although it may delay it; it exerts its contraceptive effect mainly due to its 48 action on cervical mucus and endometrial affecting sperm transport and implantation 49 50 [18]. 51 52 Animal studies demonstrated that centchroman acts by increasing the speed of 53 54 transport of the zygote through the fallopian tubes, so that it reaches the uterus early. 55 Secondly, it accelerates blastocyst formation, so that it’s hyper-mature when it 56 57 reaches the endometrium and fails to implant. Lastly, it acts by inhibiting endometrial 58 59 receptivity to blastocyst signals and by suppressing endometrial proliferation and 60
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defective endometrial decidualization, so that it is not adequately prepared to receive BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 a fertilized egg when it reaches the uterus [2, 4, 6, 45]. 6 7 3.2 PHARMACOKINETICS OF CENTCHROMAN 8 3.2.1 In non-lactating women 9 10 Five clinical trials conducted by CDRI report the pharmacokinetics of centchroman in 11 12 non-lactating women [15, 22, 26, 29, 31]. Of these, two trials report pharmacokinetics 13 14 after administration of single 30 mg dose of centchroman [26, 29], blood samples 15 were collected at regular intervals upto 672 hours post drug administration in both, 16 17 one trial reported pharmacokinetics following administration of single 60 mg dose, 18 For peer review only 19 blood samples were collected at regular intervals upto 504 hours post drug 20 21 administration [22] and one trial described pharmacokinetics after 60 mg loading dose 22 followed by 30 mg weekly dose [31]. In addition, one trial reported pharmacokinetics 23 24 following administration of 30 mg biweekly for 12 weeks (only study abstract 25 26 available) [15]. 27 The peak serum concentration (Cmax) of centchroman was reported by three of these 28 29 studies [15, 26, 31]. Cmax following a 30 mg dose is nearly half (55.5 ± 14.5 μg/L) of 30 31 that observed with a 60 mg dose, indicating Cmax is dose dependent [26]. The time 32 33 taken to reach the peak (Tmax) following 30 mg or 60 mg dose was between 4 to 8 34 hours. In the multiple dose study, it was noted that C was the same after a single 30 35 max 36 mg dose (55 ± 14.2 ng/ml) and repeated dosing did not alter the Cmax (62.4 ± 11.9 37 http://bmjopen.bmj.com/ 38 ng/ml) or Tmax (6 h) [15]. This indicated that there was no accumulation of 39 40 centchroman in the body with repeated doses. 41 The steady state minimum concentration of centchroman (Cmin) was reported in two 42 43 studies [23, 31]. The Cmin following single 30 mg dose was 16 ng/ml and it was 44 45 almost twice following 30 mg twice-weekly dose at 28 ng/ml, indicating it is dose- on September 26, 2021 by guest. Protected copyright. 46 dependent. The C at 336 hours (25.2 ± 12.4 ng/ml) was similar to C at day 80 47 min min 48 (24.2 ± 4.8 ng/ml), showing the steady state concentration of the drug was achieved at 49 50 5th 30 mg dose [15]. 51 52 Centchroman is widely distributed in the body due to its high lipid solubility. The 53 volume of distribution and drug clearance following a 30 mg (Vd/F: 1328 ± 458 L, 54 55 Cl/F 6.35 ± 1.8 L/h) or a 60 mg dose (Vd/F: 1077 L; 1909 L, Cl/F 4.4; 7.6 L/h) are 56 57 comparable, suggesting that they are dose-independent [22, 26]. One study on the 58 distribution of centchroman in the endometrium, following a 30 mg single dose 59 60 reports that centchroman is rapidly absorbed and distributed to the endometrium and 12
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at any given time, the concentration of centchroman in the uterus (mean: 152 ± 39 BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 ng/g) is 1.93 times higher than the corresponding levels in the serum (mean: 55 ± 13 6 7 μg/L) [32]. 8 Two clinical trials report the binding of centchroman to plasma proteins [19, 30]. 9 10 These show that centchroman binds strongly to serum albumin in healthy women. It 11 12 has a low affinity, high capacity binding with a dissociation (Kd) rate constant of 13 -6 14 13.19 X 10 M. The binding increases with an increase in protein content. The trial by 15 Khurana M. et al showed that with a method that includes dilution of serum, protein 16 17 binding is found to be 95.2 ± 1.1 and 88.2 ± 2.1% at 1 and 10 μg/ml. While in method 18 For peer review only 19 II, which is devoid of any dilution, protein-binding estimates were higher at 101.8 ± 20 21 1.3 and 94.9 ± 3.6% at 1 and 10 μg/ml [30]. 22 Centchroman is metabolized in the liver into active and inactive metabolites; the 23 24 active metabolite (7-desmethyl centchroman) is responsible for anti-implantation 25 26 effect [31]. 27 3.2.2 In breast feeding women 28 29 Four clinical trials report pharmacokinetics of centchroman in breast-feeding women 30 31 [24, 25, 27, 28]. These studies report the infant is exposed to a small percentage (2.5% 32 33 to 9.5%) of the maternal dose of centchroman through breast milk. The Cmax in breast 34 milk was higher (70.7 ± 27.5 μg/L) than C in the serum (60.7 ± 12.2 μg/L), and the 35 max 36 Tmax was attained later in the milk (8.50 ± 1.7 h) than in the serum (6 h) [28]. 37 http://bmjopen.bmj.com/ 38 3.3 CENTCHROMAN AS POST-COITAL CONTRACEPTIVE PILL 39 40 One randomized controlled trial among 150 women reports the effectiveness of 41 centchroman as post-coital pill within 120 hours of single unprotected intercourse 42 43 [35]. The aim of this trial was to compare the efficacy and side effects of two different 44 45 centchroman regimens with 1.5 mg single dose levonorgestrel. In this trial, women on September 26, 2021 by guest. Protected copyright. 46 were randomly allocated into three groups (50 women in each group). Women in 47 48 Group I received a 1.5 mg single dose of levonorgestrel tablet, single 60 mg dose 49 50 Group II and Group III received one 30 mg tablet, twice a day at an interval of 12 51 52 hours. The side effects reported from groups I, II and III were menstrual delay > 7 53 days (6%, 6.2%, 2%), headache (8%, 10.6%, 14.3%), abdominal pain (2%, 6.3%, 54 55 8.2%), nausea (14%, 4.3%, 4%) respectively and 10% in group I reported dizziness. 56 57 Four percent in group I, 2% users in Group II and 6% users in Group III reported 58 pregnancies, all classified as method failure (MF) (effectiveness 96%, 98%, 94%). 59 60 This trial concluded that single dose centchroman regimen (group II) is well 13
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compared to single dose regimen of levonorgestrel both in terms of efficacy and BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 safety. 6 7 3.4 EFFECTIVENESS OF CENTCHROMAN AS A WEEKLY 8 CONTRACEPTIVE 9 10 Eight studies (5 clinical trials and 3 observational studies) included in the scoping 11 12 review, report the effectiveness of centchroman [20, 21, 23, 33, 34, 36, 37, 38] (Table 13 14 3). Effectiveness in the included studies was calculated from the number of 15 pregnancies from method failure (MF). Any pregnancy associated with non- 16 17 compliance of the drug is classified as user failure (UF). 18 For peer review only 19 Clinical trials: 20 21 Four of these studies report the results from the phase III and phase IV trials on 22 centchroman. The first study is a multicentric phase III clinical trial (till June 1984), 23 24 conducted among 467 women across 10 family welfare centers [21]. Centchroman 25 26 was administered as a 30 mg once a week tablet starting on the first day of the 27 menses, and thereafter one tablet was taken on the same day every subsequent week. 28 29 An additional tablet had to be taken on the first day of every subsequent menstrual 30 31 cycle irrespective of the weekly tablet. Women had regular check-ups every month. 32 33 The duration of centchroman use in this trial ranged from 1 month to 36 months. A 34 total of 19 MF and 44 UF pregnancies occurred during the study duration (95.9% 35 36 effective). Of the 19 MF pregnancies, 14 (73.7%) occurred in the first 6 months of 37 http://bmjopen.bmj.com/ 38 centchroman use and only one (5.3%) after one year of drug use (Pearl index 4.2). 39 40 The 44 UF pregnancies occurred because the women did not adhere to the pill 41 schedule, with 20 pregnancies (45.5%) occurring in first 6 months, 15 pregnancies 42 43 (34%) between 7 to 12 months and 9 pregnancies (20.5%) after one year of pill use. 44
Table 3: Summary of studies on effectiveness of centchroman as a weekly contraceptive pill on September 26, 2021 by guest. Protected copyright. 45 Dosage Sample Pearl Method User Effectiveness 46 Ref* size index Failure Failure 47 48 Clinical trials 49 50 21 30 mg once a week. 1st 467 4.2 19 (4.1%) 44 (9.4%) 95.9% 51 tablet on first day of 52 menses and thereafter 53 one tablet on that day 54 every week. One 55 20 additional tablet was 648 3.7 27(4.2%) 66(10.2% 95.8% 56 taken on first day of ) 57 every subsequent 58 menses irrespective of 59 weekly tablet (phase 100 1.2 - - - 60
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III) BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 23 30 mg twice a week for 377 1.83 6 (1.6%) 24 (6.7%) 98.4% 6 3 months, followed by 7 30 mg once a week 8 9 10 11 33 30 mg twice a week for 755 (out of n.a. 20 (2.6%) - 97.4% 12 3 months, followed by 934) 13 & 30 mg once a week 14 15 34 16 17 Observational studies 18 For peer review only 19 38 30 mg twice a week for 153 2 7 (4.6%) 4 (2.6%) 95.4% 20 3 months, followed by 21 36 30 mg once a week 17 0 0 0 100% 22 23 37 27 n.a. Ineffective in 2 users 93% 24 (7%) 25 26 * The complete study titles are in the reference section. 27 28 The second study is an extension of the phase III multicentric clinical trial, and 29 30 reports the results in two parts: a) phase III trial till November 1986 and b) extended 31 phase III clinical trial (April 1987 to November 1988) [20]. In the study (till 1986), 32 33 648 women were recruited from 10 family welfare centres. The dosage schedule of 34 35 centchroman was same as the phase III trial [21]. The duration of pill use ranged from 36
1 month to 52 months. Twenty-seven MF and 66 UF pregnancies occurred in the http://bmjopen.bmj.com/ 37 38 study duration (95.8% effective)/ pearl index of 3.7. Among the 27 MF pregnancies, 39 40 19 (70%) occurred in the first 5 months and 4 (15%) occurred after one year of 41 42 centchroman use. For the extended phase (April 1987 to November 1988), 100 43 women were recruited in 5 additional centres. The details of number of pregnancies in 44 45 the extended phase are unavailable, however pearl index is reported as 1.2. on September 26, 2021 by guest. Protected copyright. 46 47 Phase IV clinical trial (post-marketing trial) was initiated in 2009, across 18 Human 48 49 reproductive research centers (HRRC) of ICMR, India [33, 34]. It was a non- 50 randomized clinical trial; with Cu-T users being the comparison group. The dosage 51 52 schedule for phase IV was 30 mg centchroman twice a week for 12 weeks followed 53 54 by once weekly 30 mg thereafter. The trial enrolled 2087 women (934 with 55 centchroman and 1153 with Cu-T). The interim results of this phase (on 755 56 57 centchroman users) reveal 20 MF pregnancies (97.4% effective). The detailed results 58 59 of this phase are neither published nor available on request. 60
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One conference paper [23] reports a clinical trial among 377 women to study the BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 effectiveness of centchroman using the schedule: 30 mg centchroman twice a week 6 7 for 12 weeks followed by 30 mg once a week. The study duration ranged from 1 to 27 8 months. 6 MF and 24 UF were reported during the study duration (effectiveness: 9 10 98.4%). Of the 6 MF, 2 (33%) failures occurred during the first month, 2 (33%) at 3 11 12 months and one (17%) each at 9 and 15 months. 13 14 Observational studies: 15 Additionally, three observational studies report effectiveness of centchroman ranging 16 17 between 93-100% (table 3). In the first study, 153 women were followed up for 12 18 For peer review only 19 months, of which 11 women became pregnant (4.6% MF and 2.6% UF). Majority 20 21 (81%) of pregnancies occurred during first 6 months while all occurred within 9 22 months of initiation of the pill [38]. 23 24 In the second study, 27 women were followed up for 8 months; effectiveness was 25 26 93% [37]. The authors did not report details of MF or UF. In the third study, 17 27 women were followed for 12 months; effectiveness was 100% [36]. 28 29 3.5 SIDE EFFECTS OF CENTCHROMAN USE 30 31 Thirteen studies [17, 18, 20, 21, 23, 35, 36, 37, 38, 39, 40, 41, 42] report side effects 32 33 from centchroman use as a weekly contraceptive pill (Table 4 and 5). We are 34 reporting frequently reported side effects under the following headings: menstrual 35 36 irregularities, other side effects, and changes on ultrasound examination. 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
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1 2 3 4 5 Table 4: Summary of studies on other side effects with centchroman use (percentage of women with the side effects) 6 Ref.* Sample Duration of use (dosage) Nausea/ Headache Backache Giddiness Abdomina Fever Low Breast 7 size vomiting (%) (%) (%) l pain (%) (%) Hemoglobin tenderness 8 (%) (%) (%) 9 17 23 Phase I trial: Single dose of dose ranging from + + - + - - - - 10 5-320mg 11 28 30 days (either 60 or 120 mg) - + (10.7%) + (7.1%) + (7.1%) - + - - 12 For peer review only (7.1%) 13 40 1 7 years (30 mg weekly once) ------+ - 14 35 Group Single dose (group 1: 60 mg, group2: 30 mg + + - - + - - + 15 1: 49 two tabs taken 12 hours apart) Group Group 1: Group 1: Group 2:
16 Group 1: (10.6%); (6.3%);http://bmjopen.bmj.com/ (2%) 17 2: 47 (4.3%); Group 2: Group 2: 18 Group (14.3%) (8.2%) 19 2: (4%) 20 18 Group 2 months (group A: 120 mg/ week, group B: ------21 A: 6 60 mg/ week) 22 Group 23 B: 4
24 41 1 10 years (30 mg) - - - - - on September 26, 2021 by guest. Protected copyright. - + - 25 38 153 100%- 3 months, 97% - 6 months, 93%- 9 + + - + - - - - 26 months, 85%- 12 months (30 mg twice weekly (0.7%) (0.7%) (1.3%) 27 for 3 months followed by weekly 30 mg) 28 39 25 12 months (30 mg twice weekly for 3 months - - - + - - - 29 followed by weekly 30 mg) At 3 months: (8%) 30 At 6 months: (12%) 31 42 1 24 months (60 mg twice weekly for 3 months ------+ - 32 followed by weekly 30 mg) 33 37 27 1-6 months- 18, 7-12 months-6, >12 months - - + - + + - + - 34 3 (30 mg twice weekly for 3 months followed (3.7%) (3.7%) (11%) 35 by weekly 30 mg) 36 36 17 12 months (30 mg twice weekly for 3 months ------followed by weekly 30 mg) 37 21 467 30 mg once a week (phase III multicentric + - - - - + - - 38 39 40 41 42 17 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from
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1 2 3 4 5 trial up till June 1984) (0.2%) (0.4%) 6 20 648 a. 30 mg once a week (phase III multicentric + + - + - - - - 7 trial till November 1986) b. and extended (0.2%) (0.8%) (0.8%) 8 100 phase III trial (April 1987 to November 1988) ------9 10 23 377 30 mg twice a week for 3 months, followed by ------11 30 mg once a week 12 * Note: + indicates yes and - indicates no. ForThe complete studypeer titles are in the referencereview section. only 13 14 15 Table 5: Summary of studies on menstrual irregularities with centchroman use
16 http://bmjopen.bmj.com/ 17 Ref* Dosage of centchroman Sample Short cycle ≤ 20 Prolonged Scanty Ameno Menstrual Menstrual Menstrual Continuous 18 size days cycle > 45 bleeding (1 rrhea delay > 7 delay > 15 delay > 30 bleeding 19 days or 2 days) days days days 20 17 Phase I trial-60 mg-10 women, 120 28 60 mg: 10% - - - - 60 mg: 120 mg: - 21 mg- 8 women, placebo-10 women 120 mg: 12.5 % 10% 12.5% 22 40 30 mg once per week 1 ------100%; 23 duration 20 days 24 on September 26, 2021 by guest. Protected copyright. 25 35 Group 1: Single 60 mg 150 - - - - Group 1: 6.3% - - - 26 Group 2: two doses of 30 mg 12 hour Group 2: 2% 27 apart 28 18 Group A: 120 mg/ week 10 (A- - - - - Group A: 50% - - - 29 Group B: 60 mg / week 6, B-4) Group B: 25% 30 41 Unsupervised and irregular dose (30 1 ------100%; mg) duration 45 31 days 32 38 30 mg twice a week for 3 months, 153 - 26% 12% 7% - - - 0.6% 33 followed by 30 mg once a week 34 39 30 mg twice a week for 3 months, 25 8% 16% - - - - 16% - 35 followed by 30 mg once a week 36 42 60 mg twice weekly for 3 months 1 ------100%, 37 followed by once weekly for next duration 10 38 39 40 41 42 18 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from
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1 2 3 4 5 three months. days 6 37 30 mg twice a week for 3 months, 27 4 women with menstrual irregularities (14.8%) 7 followed by 30 mg once a week 8 36 30 mg twice a week for 3 months, 17 - 3% 37.6% - - - - 1% 9 followed by 30 mg once a week 10 21 30 mg once a week (phase III 467 5% 10% ------11 multicentric trial up till June 1984) 12 20 a. 30 mg once a week (phase III 648 4.21% 8.84% ------multicentric trial till November 1986)For peer review only 13 b. and extended phase III trial (April 14 100 4% 10% ------1987 to November 1988) 15 23 30 mg twice a week for 3 months, 377 2.7% 3.7% ------
16 http://bmjopen.bmj.com/ followed by 30 mg once a week 17 The complete study titles are in the reference section. 18 * 19 20 21 3.5.1 Menstrual irregularities 22 23 The most frequent side effect among centchroman users is menstrual irregularities like: short cycles lasting < 20 days (reported by 4 studies; 4%,
24 5%, 3%, 8% users) [20, 21, 23, 39], prolonged cycles > 45 days (6 studies; 8.8%, 10%, 10%, 3%, 3.7%, 26%, on September 26, 2021 by guest. Protected copyright. 16% users) [20a, 20b, 21, 23, 36, 25 26 38, 39], scanty bleeding lasting 1 or 2 days (2 studies; 12%, 36.7% users) [36, 38], and menstrual delay > 30 days (1 study; 15 % users) [39]. 27 28 Five studies report continuous bleeding as a side effect. Of these, three are case reports of women on unsupervised long-term use of the pill, 29 30 presenting with continuous bleeding of 10 to 45 days duration [40, 41, 42]. Two other studies report continuous bleeding among 1% of 31 centchroman users [36, 38]. The Indian National guidelines on oral contraceptive use, report menstrual delay among 8% of centchroman users, 32 33 and state it typically occurs in the first three months of centchroman use [4]. 34 35 36 37 38 39 40 41 42 19 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 20 of 33
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3.5.2 Other side effects BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 The phase I trial on centchroman, initiated in 1970’s included 51 participants (23 6 7 females and 28 males) [17]. At the end of this phase, it was concluded that a dose of 8 5-320 mg centchroman is well tolerated by humans, because it did not show any 9 10 major side effect or any abnormality in laboratory parameters. 11 12 Phase III multicentric trials (till 1984) reported one women with 8 kg weight gain 13 14 over 34 months period of drug use, one of loose stools, vomiting and two with fever 15 [21]. In the phase III (till 1986) five women complained of giddiness, five of 16 17 headache, one of anorexia, one of loose motions and vomiting and one ectopic 18 For peer review only 19 pregnancy [20]. 20 21 The other side effects reported from included studies were: headache (2 studies; 1% 22 and 4% users) [37, 38], giddiness (2 studies; 1.3% and 12%) [37, 38], nausea (1 study, 23 24 0.7%) [38], and giddiness with abdominal pain (1 study; 8% at 3 months and 12% 25 26 users at 6 months) [39]. In addition, three case reports provide detail on women with 27 complaints of continuous bleeding and on investigation are found to be severely 28 29 anemic (Hb: 4 g/dl, 5 g/dl and 7 g/dl) [40, 41, 42]. Further, an observational study 30 31 reported anemia in 11% users [37]. 32 33 3.5.3 Changes in the ovaries and uterus 34 Seven studies [27, 34, 36, 38, 40, 41, 42] in the review report the ultrasound findings 35 36 among centchroman users (table 6). The main findings reported by these studies are: 37 http://bmjopen.bmj.com/ 38 (a) Three case reports found a bulky uterus with distorted endometrial cavity [40, 41, 39 40 42]. (b) One study found ovarian enlargement among 18% of the users [38]. In 41 another study among the 175 women who were followed up for 40 months on 42 43 centchroman, 15% showed ovarian enlargement. The enlargement was unilateral, 44 45 transient and never persisted and got resolved despite centchroman therapy [27]. One on September 26, 2021 by guest. Protected copyright. 46 study among 17 women, however, showed no changes in ovaries [36]. The 47 48 preliminary results of the phase IV trial report 4 women with ovarian cysts < 5 cms 49 50 and 2 women with cysts > 5 cms [34]. 51 Table 6: Summary of studies on ultrasound findings among centchroman users 52 53 Ref* No. of women Dosage of centchroman Duration of Ultrasound findings 54 who underwent Centchroman 55 USG intake 56 40 1 30 mg once a week 7 years Enlarged uterus with well 57 delineated endometrial thickness 58 & a mixed echogenic collection 59 in a distorted endometrial cavity 60 41 1 30 mg once a week 10 years Mixed echogenic collection in a
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(irregular and distorted endometrial cavity of a BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 unsupervised) bulky uterus (101 X 84 mm). 5 Ovaries were normal 6 38 28 (of 153 30 mg twice weekly for 3-12 months 20 women had normal looking 7 participants) 3 months, followed by ovaries, 8 30 mg weekly once 4 (14.2%) women had follicular 9 cysts 10 4 (14.2%) women had corpus 11 luteal cysts 12 No cyst was bigger than 2.5-3 13 cm 14 42 1 60 mg twice weekly for 2 years Bulky uterus with 8X4 cm hyper 15 3 months followed by echoic area with increased AV 16 once weekly channels within it. 17 (unsupervised use) Endometrium was not separately 18 For peer review only made out 19 36 17 30 mg twice weekly for 12 months No significant ovarian 20 3 months followed by 30 enlargement was detected during 21 mg once weekly centchroman use 22 23 64 (of 377 30 mg twice a week for 12-30 months Two cases of enlarged ovaries 23 participants) 3 months, followed by One showed enlarged ovary at 6 24 30 mg once a week months and one at 12 months 25 In both cases, enlargement was 26 due to mature unruptured 27 follicle 28 On subsequent examination at 29 12 and 20 months, ovaries were 30 normal. 31 27 175 30 mg twice a week for Upto 40 months 15% of women had ovarian 32 3 months, followed by enlargement 33 30 mg once a week Enlargement was unilateral and 34 transient 35 * The complete study titles are in the reference section. 36 37 No additional data is available. http://bmjopen.bmj.com/ 38 4. DISCUSSION 39 40 This is the first scoping review that systematically identified and summarized the 41 42 studies on centchroman, as a contraceptive pill. Our primary aim for this scoping 43 review was to collate the overall evidence available on the current state of knowledge 44 45 on mechanism of action, pharmacokinetics, side effects and effectiveness of on September 26, 2021 by guest. Protected copyright. 46 47 centchroman as a weekly and post-coital contraceptive pill. The methods used 48 49 throughout the different stages of the review were rigorous, transparent and the 50 process is documented in sufficient detail to replicate the research approach. In 51 52 addition, we interviewed a product manager from the pharmaceutical company that 53 54 manufactures centchroman in India to gain insight on sales and marketing of 55 56 centchroman. He said that currently centchroman is only marketed in India as a 57 weekly contraceptive pill, though in the past it has been sold as an emergency post- 58 59 coital pill and was also marketed in South America for a short period. On 60
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effectiveness, with perfect use the failure rate of centchroman was 1-2%, but with BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 typical use the failure rate increases to 6-7%. We here recognize the potential conflict 6 7 of interest, as the pharmaceutical manager may be biased in responses to boost his 8 company sales. 9 10 This scoping review identified 33 primary research papers, annual reports, theses and 11 12 national guidelines on centchroman, from India published between 1976 and 2019. 13 14 Only two studies in our review report the mechanism of action of centchroman in 15 women (sample size: 8,10) [16, 18]. 16 17 Eight studies report the effectiveness of centchroman as a weekly contraceptive pill 18 For peer review only 19 involving a total of 2544 women. The reported effectiveness ranged from 96% to 98% 20 21 in clinical trials and 93% to 100% in observational studies. This review thus suggests 22 that the effectiveness of centchroman as a weekly contraceptive is slightly lower than 23 24 what is noted as 98-99% in the Indian National guidelines [4]. Only one RCT among 25 26 150 women reports the effectiveness of Centchroman as a post-coital pill [35]. It was 27 98% effective when taken as a single 60 mg within 120 hours of unprotected 28 29 intercourse. The detailed results of phase IV trials would provide conclusive 30 31 information on effectiveness. 32 33 Thirteen studies report side effects of centchroman use as an oral contraceptive. 34 Continuous bleeding and prolonged cycles > 45 days were the two most commonly 35 36 reported side effects among centchroman users. The side effects profile is similar to 37 http://bmjopen.bmj.com/ 38 that seen with hormonal contraceptive pills. The studies on side effects are of low 39 40 quality with small sample size. The largest sample for observational studies was 153 41 women and maximum follow up was of 12 months. This limits meaningful 42 43 conclusions to be drawn. Though the phase IV drug trial included a large sample (934 44 45 users), but the detailed results of this phase are not published and were not available on September 26, 2021 by guest. Protected copyright. 46 on request hence could not be used in the review. To the best of our knowledge there 47 48 has been no published scientific trial comparing side effects of centchroman to other 49 50 safe and effective oral contraceptive pills. There is a need for studies with robust 51 52 study designs comparing centchroman with other hormonal methods. 53 The Indian National guidelines [4] have menstrual delay among 8% of the 54 55 centchroman users, and do not mention any other side effects. We suggest the 56 57 guidelines be updated to include other side effects as well, so that the health providers 58 can comprehensively counsel the women on the possible side effects during 59 60 counseling. 22
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5. CONCLUSIONS BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 Our scoping review provides a broad and a comprehensive review of currently 6 7 available literature on centchroman, when used as a contraceptive pill. The review 8 demonstrates that despite evidence on effectiveness of centchroman, more research is 9 10 needed on side effects and mechanism of action. Insufficient evidence exists on its 11 12 use as a post-coital contraceptive pill. Robust study designs are needed such as RCT 13 14 or longitudinal studies to compare effectiveness and safety of centchroman with other 15 short-term modern contraceptives such as combined hormonal oral pills (COCs) or 16 17 progesterone only pills (POPs) contraceptives. It is clear that there are extensive gaps 18 For peer review only 19 in the literature that warrant further studies, both in Indian and International settings. 20 21 The uncertainty and diversity of side effects and effectiveness in the studies across 22 India, implies lack of body of evidence to make global recommendations on 23 24 centchroman, a contraceptive method that is licensed and used in the second most 25 26 populous country in the world. 27 6. ETHICAL APPROVAL AND CONSENT TO PARTICIPATE 28 29 Not applicable 30 31 7. CONSENT FOR PUBLICATION 32 33 All authors read and approved the final manuscript. This review contains the 34 collective views of an international group of experts, and does not necessarily 35 36 represent the decisions or the stated policy of the World Health Organization. 37 http://bmjopen.bmj.com/ 38 8. COMPETING INTERESTS 39 40 The funding sources did not play a role in the study design, analysis and interpretation 41 of data, in the writing of the report, or in the decision to submit the article for 42 43 publication. The conclusions and opinions expressed here are those of the authors and 44 45 not necessarily those of the funder. on September 26, 2021 by guest. Protected copyright. 46 9. FUNDING 47 48 The UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, 49 50 Development and Research Training in Human Reproduction (HRP), a co-sponsored 51 52 program executed by the WHO, funded this work 53 10. AUTHOR’S CONTRIBUTIONS 54 55 The idea for this publication was conceived by RK and JK. RK and KPA prepared the 56 57 first draft. MA, CAJ, KM and JK provided significant contributions to the draft. All 58 authors reviewed the draft manuscript and approved the final manuscript for 59 60 publication. 23
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11. DATA AVAILABILITY BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 All data relevant to the study are included in the article or uploaded as supplementary 6 7 information 8 12. ACKNOWLEDGEMENTS 9 10 We would like to thank Mr. Tomas John Allen, librarian at WHO Geneva for his 11 12 assistance in developing a search strategy and running the search for this scoping 13 14 review. We would like to thank Drs. Manisha Malhotra, Bulbul Sood, Saswati das 15 (JHPIEGO), Shalini Singh (ICMR) for their support in identifying the stakeholders 16 17 and for their valuable suggestions on the protocol and the initial draft of this scoping 18 For peer review only 19 review. We would also like to thank all the stakeholders who participated in the 20 21 interviews and shared their experiences with centchroman use. 22 ABBREVIATIONS 23 24 CDRI-Central Drug Research Institute 25 26 Cmax- Peak serum concentration of Centchroman 27 Cmin- Steady state minimum concentration of centchroman 28 29 COCs- Combined hormonal oral pills 30 31 EMA- European Medicines Agency 32 33 FDA- Food and Drug Administration 34 HLL- Hindustan Latex Limited 35 36 ICMR-Indian Council of Medical Research 37 http://bmjopen.bmj.com/ 38 INN- International non-proprietary name 39 40 Kd- Dissociation rate constant 41 MF- Method Failure 42 43 MeSH- Medical Education Subject Headings 44 45 POPs- Progesterone only pills on September 26, 2021 by guest. Protected copyright. 46 RCT- Randomized control trial 47 48 SERM- Selective Estrogen Receptor Modulator 49 50 SRH- Sexual and reproductive health 51 52 UNFPA- United Nations Population Fund 53 USAID- United States Agency for International Development 54 55 USG- Ultrasonography 56 57 UF- User Failure 58 Vd- Volume of Distribution 59 60 WHO- World Health Organization 24
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REFERENCES: BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 1. Singh MM. Centchroman, a selective estrogen receptor modulator, as a 6 7 contraceptive and for the management of hormone-related clinical disorders. 8 Medicinal Research Reviews2001;21(4):302-347. 9 10 2. Population foundation of India. Spacing methods of family planning. Available 11 12 from http://populationfoundation.in/files/fileattached/Fileattached-1492415902- 13 th 14 Family_Planning_methods_Eng.pdf. Cited 17 November 2017 15 3. Kamboj V, Ray S, Anand N. Centchroman: A safe reversible post-coital 16 17 contraceptive with curative and prophylactic activity in many disorders. Frontiers 18 For peer review only 19 in Bioscience(Elite edition)2018;10:1-14 20 21 4. Family planning division, Ministry of Health and Family welfare, Government of 22 India. Reference manual for Oral contraceptive pills. New Delhi: Ministry of 23 24 Health and Family welfare -Government of India; 2016. 25 26 5. D. Balasubramanian. On conception and contraception: The story of Saheli; The 27 Hindu: 24th June 2017. Available from https://www.thehindu.com/sci- 28 29 tech/science/on-conception-and-contraception-the-story-of- 30 31 saheli/article19140909.ece. Cited 28th June 2018. 32 33 6. Lal J. Clinical pharmacokinetics and interaction of centchroman - A mini review. 34 Contraception2010;81(4):275-280. 35 36 7. World Health Organization. WHO drug information: Recommended INN list 34 37 http://bmjopen.bmj.com/ 38 international nonproprietary names for pharmaceutical substances. Volume 8, 39 40 Number 4. Geneva: World Health Organization; 1994. 41 8. Chawla PC. CSIR’s novel contraceptive drug- a woman’s true Saheli. In: Chawla 42 43 PC, editor. CSIR News: Progress, promise and prospects. New Delhi: NISCAR 44 45 Press; 2010,Volume 60(No. 15 & 16):171-172. on September 26, 2021 by guest. Protected copyright. 46 9. Population Research Institute. News from Latin America. One less weapon 47 48 against the unborn: The abortion pill gets pulled from market. January 1 2010. 49 50 Population Research Institute. Available from https://www.pop.org/news-from- 51 52 latin-america-one-less-weapon-against-the-unborn-the-abortion-pill-gets-pulled- 53 from-the-market/. Cited 23rd November 2017 54 55 10. HLL Lifecare Limited. Innovating for healthy generations. Annual report 2013- 56 57 2014. Available from 58 http://www.lifecarehll.com/page/render/reference/Annual_Report. Cited 20th 59 60 October 2017 25
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regulation and reproduction, Eds: CP Puri, PFA VanLook New Delhi, Wiley BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 Eastern Ltd.1994:61-68 6 7 24. Paliwal JK, Grover PK, et al. Excretion of centchroman in breast milk. British 8 Journal of Clinical Pharmacology1994;38(5):485-486. 9 10 25. Gupta RC, Paliwal JK, Nityanand S, et al. Centchroman: A new non-steroidal oral 11 12 contraceptive in human milk. Contraception1995;52(5):301-305. 13 14 26. Lal J, Asthana OP, Nityanand S, et al. Pharmacokinetics of centchroman in 15 healthy female subjects after oral administration. Contraception1995;52(5):297- 16 17 300. 18 For peer review only 19 27. Nityanand S, Gupta RC, Kamboj VP, et al. Centchroman: current status as a 20 21 contraceptive. Indian progress in family welfare: clinical research on maternal and 22 child health & contraception, Eds: SC dawn, A Misra Calcutta, Dawn 23 24 books1995:26-31. 25 26 28. Gupta RC, Nityanand S, Asthana OP, et al. Pharmacokinetics of centchroman in 27 nursing women and passage into breast milk. Clinical Drug 28 29 Investigation1996;11(5):305-309. 30 31 29. Lal J, Nityanand S, Asthana OP, et al. Comparative bioavailability of two 32 33 commercial centchroman tablets in healthy female subjects. Indian Journal of 34 Pharmacology1996;28(1):32-34. 35 36 30. Khurana M, Paliwal JK, Kamboj VP, et al. Binding of centchroman with human 37 http://bmjopen.bmj.com/ 38 serum as determined by charcoal adsorption method. International Journal of 39 40 Pharmaceutics1999;192(2):109-114. 41 31. Lal J, Nityanand S, Asthana OP, et al. Optimization of contraceptive dosage 42 43 regimen of Centchroman. Contraception2001;63(1):47-51. 44 45 32. Khurana M, Lal J, Kamboj M, et al. Uptake of centchroman by the human uterus. on September 26, 2021 by guest. Protected copyright. 46 Clinical Drug Investigation2002;22(10):715-718. 47 48 33. Indian Council of Medical Research (ICMR). Reproductive Health: Annual report 49 50 2009-10. Available from http://www.icmr.nic.in/annual/2009-10/english/rh.pdf. 51 th 52 Cited 20 November 2017 53 34. Indian Council of Medical Research (ICMR). Reproductive Health: Annual report 54 55 2010-11. Available from http://www.icmr.nic.in/annual/2010- 56 th 57 11/English%20Annual%20Report/rh.pdf. Cited 20 November 2017 58 59 60
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35. Mittal S, Sehgal R, Jindal VI, et al. Single dose levonorgestrel and two regimens BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 of centchroman for emergency contraception. Journal of the Turkish German 6 7 Gynecology Association2008;9(3):132-137. 8 36. Tandon D. Effect of centchroman on biochemical profile, ovulation and ovarian 9 10 size. Masters of Surgery Thesis. Bundelkhand University. 1992. Available from 11 12 https://ia601601.us.archive.org/16/items/in.ernet.dli.2015.269787/2015.269787.Ef 13 14 fect-Of.pdf 15 37. Ghosh S. Prospective observational study of the pattern of usage of oral 16 17 contraceptive pills. Masters of Pharmacy thesis. 2014. Available from 18 For peer review only 19 http://jadunivdspace.jdvu.ac.in/bitstream/123456789/29440/1/Acc.%20No.%20D 20 21 C%201823.pdf 22 38. Nair HS, Jayasimhan P. A prospective study of centchroman users with special 23 24 reference to its contraceptive benefit. Journal of evidence based medicine and 25 26 healthcare2016;3(98):5374-5380. 27 39. Agrawal P, Kushwa V, Mangal BK. Evaluation of safety profile of centchroman 28 29 for contraceptive purpose. National journal of medical and allied 30 31 sciences2016;5(2):41-44. 32 33 40. Malhotra KP, Sherpa M, Bhatia A. Centchroman: Is unsupervised long-term use 34 warranted? Case report. European Journal of Contraception and Reproductive 35 36 Health Care2011;16(5):403-406. 37 http://bmjopen.bmj.com/ 38 41. Agarwal R., Radhakrishnan G, Radhika AG, et al. Abnormal uterine bleed- an 39 40 adverse event of long-term centchroman use? Indian journal of maternal and 41 child health2014;16(2):1-7. 42 43 42. Padmaja A, Vemulapalli P, Jaya Prada Devi K. Rare case of endometrial 44 45 hyperplasia following unsupervised prolonged use of ormeloxifene. IOSR Journal on September 26, 2021 by guest. Protected copyright. 46 of dental and medical sciences2013;5(4):55-57 47 48 43. Family planning division, Ministry of Health and Family welfare, Government of 49 50 India. An update on new family planning methods for ASHA. New Delhi: 51 52 Ministry of Health and Family welfare -Government of India; 2017. 53 44. Ministry of Health and family welfare, Government of India, United Nations 54 55 Population Fund. Contraceptive updates. Reference manual for doctors. New 56 57 Delhi: Ministry of Health and Family welfare; 2005. 58 59 60
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45. Central drug research institute, Lucknow. Annual report 2016-17. Available from BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from 4 5 http://www.cdri.res.in/Annual_Reports/Annual_Report_2016_17.pdf. Cited 21st 6 7 October 2017 8 9 10 11 12 13 14 15 16 17 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
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 Key milestones on evolution of centchroman 20 21 22 23 24 25 26 27 28 29 30 31 32 33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40 41 on September 26, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 31 of 33 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 http://bmjopen.bmj.com/ 34 35 Prisma flow chart 36 37 38 39 40 41 on September 26, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 32 of 33 BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from
1 2 3 Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for 4 Scoping Reviews (PRISMA-ScR) Checklist 5 6 REPORTED SECTION ITEM PRISMA-ScR CHECKLIST ITEM 7 ON PAGE # 8 TITLE 9 Title 1 Identify the report as a scoping review. 1 10 ABSTRACT 11 Provide a structured summary that includes (as 12 applicable): background, objectives, eligibility criteria, Structured 13 2 sources of evidence, charting methods, results, and 2-3 summary 14 conclusions that relate to the review questions and 15 objectives. 16 INTRODUCTION For peer review only 17 Describe the rationale for the review in the context of what is already known. Explain why the review 18 Rationale 3 4-5 19 questions/objectives lend themselves to a scoping 20 review approach. 21 Provide an explicit statement of the questions and 22 objectives being addressed with reference to their key 23 Objectives 4 elements (e.g., population or participants, concepts, and 5 24 context) or other relevant key elements used to 25 conceptualize the review questions and/or objectives. 26 METHODS 27 Indicate whether a review protocol exists; state if and Protocol and where it can be accessed (e.g., a Web address); and if 28 5 - 29 registration available, provide registration information, including the registration number. 30 Specify characteristics of the sources of evidence used 31 Eligibility criteria 6 as eligibility criteria (e.g., years considered, language, 7 32
and publication status), and provide a rationale. http://bmjopen.bmj.com/ 33 Describe all information sources in the search (e.g., 34 Information databases with dates of coverage and contact with 7 6 35 sources* authors to identify additional sources), as well as the 36 date the most recent search was executed. 37 Present the full electronic search strategy for at least 1 38 Search 8 database, including any limits used, such that it could be 6 39 repeated. 40
Selection of on September 26, 2021 by guest. Protected copyright. State the process for selecting sources of evidence (i.e., 41 sources of 9 7 screening and eligibility) included in the scoping review. 42 evidence† 43 Describe the methods of charting data from the included 44 sources of evidence (e.g., calibrated forms or forms that 45 Data charting have been tested by the team before their use, and 10 8 46 process‡ whether data charting was done independently or in 47 duplicate) and any processes for obtaining and 48 confirming data from investigators. 49 List and define all variables for which data were sought Data items 11 8 50 and any assumptions and simplifications made. If done, provide a rationale for conducting a critical 51 Critical appraisal of appraisal of included sources of evidence; describe the 52 individual sources 12 - methods used and how this information was used in any 53 of evidence§ 54 data synthesis (if appropriate). Describe the methods of handling and summarizing the 55 Synthesis of results 13 8 56 data that were charted. 57 58 59 1 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 33 of 33 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-030373 on 7 October 2019. Downloaded from
1 2 3 REPORTED SECTION ITEM PRISMA-ScR CHECKLIST ITEM 4 ON PAGE # 5 RESULTS 6 Give numbers of sources of evidence screened, Selection of 7 assessed for eligibility, and included in the review, with sources of 14 8 8 reasons for exclusions at each stage, ideally using a flow evidence 9 diagram. 10 Characteristics of For each source of evidence, present characteristics for 11 sources of 15 9-11 which data were charted and provide the citations. 12 evidence 13 Critical appraisal If done, present data on critical appraisal of included within sources of 16 - 14 sources of evidence (see item 12). 15 evidence 16 Results of For peerFor each included review source of evidence, only present the 17 individual sources 17 relevant data that were charted that relate to the review 11-21 18 of evidence questions and objectives. Summarize and/or present the charting results as they 19 Synthesis of results 18 11-21 20 relate to the review questions and objectives. 21 DISCUSSION 22 Summarize the main results (including an overview of Summary of concepts, themes, and types of evidence available), link 23 19 21-22 24 evidence to the review questions and objectives, and consider the 25 relevance to key groups. 26 Limitations 20 Discuss the limitations of the scoping review process. 23 27 Provide a general interpretation of the results with 28 Conclusions 21 respect to the review questions and objectives, as well 23 as potential implications and/or next steps. 29 FUNDING 30 Describe sources of funding for the included sources of 31 evidence, as well as sources of funding for the scoping 32 Funding 22 24 review. Describe the role of the funders of the scoping http://bmjopen.bmj.com/ 33 review. 34 JBI = Joanna Briggs Institute; PRISMA-ScR = Preferred Reporting Items for Systematic reviews and Meta-Analyses 35 extension for Scoping Reviews. 36 * Where sources of evidence (see second footnote) are compiled from, such as bibliographic databases, social media 37 platforms, and Web sites. 38 † A more inclusive/heterogeneous term used to account for the different types of evidence or data sources (e.g., 39 quantitative and/or qualitative research, expert opinion, and policy documents) that may be eligible in a scoping review as opposed to only studies. This is not to be confused with information sources (see first footnote). 40
‡ The frameworks by Arksey and O’Malley (6) and Levac and colleagues (7) and the JBI guidance (4, 5) refer to the on September 26, 2021 by guest. Protected copyright. 41 process of data extraction in a scoping review as data charting. 42 § The process of systematically examining research evidence to assess its validity, results, and relevance before 43 using it to inform a decision. This term is used for items 12 and 19 instead of "risk of bias" (which is more applicable 44 to systematic reviews of interventions) to include and acknowledge the various sources of evidence that may be used 45 in a scoping review (e.g., quantitative and/or qualitative research, expert opinion, and policy document). 46 47 48 From: Tricco AC, Lillie E, Zarin W, O'Brien KK, Colquhoun H, Levac D, et al. PRISMA Extension for Scoping Reviews (PRISMA- 49 ScR): Checklist and Explanation. Ann Intern Med. ;169:467–473. doi: 10.7326/M18-0850 50 51 52 53 54 55 56 57 58 59 2 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml