A multicentred phase III comparative clinical trial of depot-medroxyprogesterone acetate given three-monthly at doses of 100mg or 150mg: 1. Contraceptive efficacy and side effects

CONTRACEPTION

A MULTICENTRED PHASE ITI COMPARATIVE CLTNTCAL TKIAL OF DEPOT-MEDROXYPROGESTERONE ACETATE GIVEN THREE-MONTHLY AT DOSES OF 1OOMG OR 15DMG: 1. CONTRACEPTIVE EFFICACY AND SIDE EFFECTS WORLD Task

Force

HEALTH

OKGANIZATION

on Long-Acting Systemic Agents for Fertrlrty Kegulatlon Specral Programme of Researcn, Development and Research Trarnlng rn Human Reproduction

S. Said and K. Omar Department of Obstetrrcs University of Alexandria,

and Gynaecology, Shatby Alexandrra, Egypt

Maternity

Hosprtal,

Suporn Koetsawang, Orawan Kiriwat and Yuwadee Srlsatayapan Family Planning Research Unrt, Srriraj Hospital, Mahrdol University, Bangkok, Thailand A. Kazl and F. Ajmal Natronal Kesearcn Instrtute

of Fertrlrty

Control,

H. H. Wynter Advanced Tralnrng and Research Unit rn Fertrlrty of the West Indres, Krngston, Jamaica A. Pretnar-Darovec Unlversrty C~LIILC of Obstetrics

and Gynaecolugy,

Karachr,

Management,

LJubljana,

PaKlStarl

Universr:y

Yugoslavia

1. B. Benitez, J. de La Cruz, and R. Apelo Keproductrve Biology Centre, Department of Obstetrics and Gynaecology, Universrty of the Phrlipprnes, Manila, the College of Medicine, Phlllpprnes L. Kovacs and S. Koloszar Department of Obstetrics and Gynaecology, Szeged, Szeged, Hungary

Unlverslty

Medical

School

of

ii.

Busca, P. E. Hall and D. Machin" Special Programme of Research, Development and Research Training in Human Reproductron, World Health Organrzatrun, Geneva, Swrtzerland -'-also Medlcal Southampton,

Statistics and Computrng, United Krngdom

University

of Southampton,

Reprrnt requests and address for correspondence: Peter E. Hall, Special Programme of lieSearch, Development and Research Training r.n Human Reproduction, World Health Organization, 1211 Geneva 27, Switzerland Submitted for publication August 7, 1986 Accepted for publication September 17, 1986

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1986 VOL. 34 NO. 3

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CONTRACEPTION

ABSTRACT

Two dosages of depot-medroxyprogesterone acetate (DMPA), 1OUmg and 150mg given every 90 days, were compared in two groups of women with regard to effectiveness, reported complaints and reasons for dlscontlnuatlon. A total of 1216 women were recruited Into a seven-centre, multinational, randomized cllnical trial. Follow-up was for a period of one year and resulted in a total of 5507 woman-months of experience of 1OOmg DMPA and 5429 woman-months of experience of the 150mg dose. The study showed little difference in efficacy and side effects between the two treatment groups. Two pregnancies occurred In women receiving 1OOmg DMPA giving a Pearl Index of 0.44 per 100 woman-years. None occurred In the 15Omg group. There was no difference in the overall continuation rates between the two groups at one year, being 59.3% in the 1OUmg group and 58.8% in the 150mg group. Except for discontinuation of method use for amenorrhea, the rates of all medical and non-medical reasons given for dlscontlnuation were comparable between the two treatment groups. Women's perception of lack of bleeding was reported as amenorrhea and resulted III discontinuation rates at 12 months for amenorrhea of 7.2% for women receiving 1UOmg of DMPA and 12.5% for those recelvlng the 150mg dose. Three centres, Alexandria, Karachi and Szeged, made the major contributions to this difference.

INTRODUCTION

Depot-medroxyprogesterone acetate (DMPA) was first introduced as a contraceptive in the mid-1960's and IS currently being used by some each year. Despite three million women throughout the world recent evaluations of available controversy relating to its safety, animal and human data and the study of its possible association with neoplasia, have shown DMPA to be a safe and highly effectrve injectable contraceptive (1, 2, 3). DMPA does, however, considerably disrupt normal menstrual bleeding It inrtially gives rise patterns in women using it as a contraceptive. to unpredrctable bleeding and spotting and, with increasing duration of use to amenorrhea. Such disturbances can be inconvenient and of Although DMPA appears to give rise potential concern to the woman (2). it has not been shown to impair to a delay rn the return of fertility, subsequent fertility (4). Xn its strategy issues relating to the safety and to assess the World Health efficacy of this contraceptive method, important Organization's Task Force on Long-Acting Systemic Agents for Fertility studres on the pharmacoklnetics and Regulation undertaken has

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1986 VOL. 34 NO. 3

CONTRACEPTION

pharmacodynamic effects of 25, 50, 100 and 150mg of DMPA in Mexico difference was (5)and in Thailand (6). In both studies, no significant observed in the ability of either 100 or 150mg of DMPA to inhabit there was no obvious ovulation for a minimum of 90 days. Furthermore, difference in serum peak levels of MPA between these two dosages or in the serum levels of MPA measured 90 days after the injection. It was therefore decided to compare the efficacy and the Incidence of side effects of 100 and 150mg of DMPA in a randomized Phase III clinical trial with a view to reducing the overall steroid load and less drug-induced associated with ascertaining whether this is amenorrhea or other side effects. No attempt was made to assess return of fertility in SubJeCtS participating 1n this study.

MATERIALS

AND METHODS

Preparations The preparations used in the study were 1OOmg or 150mg doses of in Depo-ProveraR (depot-medroxyprogesterone acetate, DMPA) formulated They were lml of aqueous solution as a microcrystalline suspension. provided by the Upjohn Company, Kalamazoo, Michigan, U.S.A. Design

of the study

All subjects were normal, healthy women with regular menstrual bleeding and any previous pregnancy completed more than 60 days before entry into tne study. Tne women consented voluntarily to participate injection at any time during the and were free to refuse a subsequent study. first received a screening interview and a physical The volunteers whether they conformed to the admrsslon examinat ion to ascertain criteria . Those subjects who did were admitted into the study and They received assigned at random to one of the two treatment groups. the fir:st injection within the first 5 days of the next menstrual A total of four injections were planned with follow-up at cycle. intervals of 90 -+ 7 days for one year. with a vaginal bleeding record card at Each woman was provided each go-day follow-up visit and requested to note each day on which bleeding or spotting occurred. At each follow-up visit, any complaints by the woman were elicited by indirect questioning. If a woman wished to discontinue method use for any reason or was advised to by the physicran, then a record was made of the one or two principal reasons and diastolic blood Weight, systolic given for- her discontinuation. pressures were routinely recorded at each visit. It was assumed that 1OOmg DMPA given every effective in preventing pregnancies as 150mg DMPA

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1986 VOL. 34 NO. 3

90 days would be and could replace

as it

225

CONTRACEPTION

for contraceptive use rf there was no increase ln the prevalence or as vaginal bleeding dlsturoanres. To safeguard side-effects, such against an unexpectedly high pregnancy rate, the study was to be time if the lower 95X confidence limit of the terminated at any pregnancy rate exceeded 3 pregnancies per 100 woman years. Assuming a cumulative discontinuation rate 12 months of at approximately 50X for both doses, which was observed in a previous in each group is large enough to multicentred study (21, 600 subjects in cumulative dlscontlnuatlon rates rule out any difference between doses of more than 62 (assuming test size iOX, power 80X as recommended by Makuch and Simon (8) for equivalence studies). i.Gstitutlons ln the following The study was undertaken Ln academic seven cities: AlexandrLa, Egypt; Bangbzk, Thailand; Karachi, Pakistan; Klngston, Jamaica; Ljubljana, Yugoslavia; Manila, the PhilIppines; and Recruitment began In July 1382 and the Last follow-up Szeged, Hungary. visit was completed In January 1986. In aAL, 12Lb women were admitted to the study. Statlstical

DroCedureS

The duration of method experience of the women using the two dosages was compared for each discontinuation reason by means of the logrank test as recommended by Farley (7). AL1 the logrank statistics degree of Admission quoted have one freedom. (X2R) characteristics were compared using either tne two-sample t-test or the Corresponding confidence limits are not x2 test as appropriate. quoted as the two groups were so similar In all respects. The following censoring conventlon was used in the analysis. A woman who returned late for a particular injection was credlted with protection for the whole injection Lnterval provided she actually If she refused the injection, she was credited received the injection. with protection for 97 days from her last injectlon. If a woman received an injection and was then subsequently lost to follow-up, she was not credited with any post-injectlon protection. Her experience was calculated from the date of first Injection to the date of last injection. Those women who received the first injectlon on admlssLon the second injection were and who were then lost to follow-up before therefore credited with zero protectlon. fourth be noted that once a woman received her It should injection, then the only reasons that could be recorded for withdrawing from the study were either pregnancy, losslr to follow-up, surgical fertility or the end of the study Intervention which affected her itself. Thus although a woman may have complained of heavy bleeding following the fourth injection, she could not discontinue the method Had she complained after for this reason at this stage of the trial. her third injection, she would have had the option to refuse the fourth injection and would have left the study after 9 months of method use.

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CONTRACEPTION

RESULTS

Numbers

of subjects

Table 1 shows the numbers who attended and the numbers follow-up visits.

of

at

subjects each of

recruited the four

at each centre, YO-aay scheduled

A total of 64 women visited the clinic for one unscheduled visit The total experience accummulated and one for two unscheduled visits. was >507 woman-months with the 1OOmg dose of DIMPA and 5429 woman-months wrth the L50mg dose of DMPA. Table Number

of subjects

recruited

1

and number

FOLLOW-UP VTSITS

at each visit

by centre

(montlls)

UNSCHEDULED

ADMISSTON 3

b

Y

12

12

1,216

1187

974

814

727

64

1

DMPA-LUUmg DMPA-150mg

609 607

592 595

488 4X6

414 400

367 360

3b 28

U 1

Alexandria Bangkok Karachi Kingston Ljubljana Man i 1a Szeged

lY8 2ou 196 118 lU6 2ou LJ8

lY4 lY7 188 118 102 198 190

170 150 138 106 73 179 158

152 13u 1114 101 54 150 123

1.37 LLZ 85 LUU SL 142 1UY

IU 7 18 0 6 12 11

0 0 0 0 0 1 I)

Grand

Admisslon

Total

characteristics

There were no statistically significant differences between the receiving either dose of DMPA with regard groups to the mean age, height, weight, systolic Quetelet (wergnt/heignt2), and index diastolic blooa pressure, number of live births, abortions, prevrous pregnancies, the number in each ethnic group and outcome of Last pregnancy. Tne median number of days since last pregnancy, mean age at menarche and menstrual bleeding characteristics of the women were also slmllar in each group.

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227

CONTRACEPTION

Women were asked to detail the contraceptive methods used III the two years prior to entry to the trial and to specify the last method used. the two groups. Agaln, these were similar between The reasons for dlscontinulng the last method of contraception were also recorded, 49 women reported dlscontlnuing use of the previous method because of bleeding problems and only 3 for amenorrhea. For the total study population, the mean age was 27.7 (standard deviation, 5.0) years, weight 57.1 (12.9) kg, Quetelet Index 23.1 (4.7) kg m-* and parity 3.3 (2.0). Prior to the study, the mean cycle length was 28.9 (1.8) days and the mean duration of bleeding episodes, 4.4 (1.0) days. Reasons

for discontinuation

General. The number of women who completed the study, those a) who were lost to follow-up and those who discontinued method use is shown by dosage group in Table II. Approximately 59% of the women 59.3 and 58.8% on the 100 and 150mg doses, completed the study, respectively, 7.b% were lost to follow-up and the remaining 33.3% discontinued method use for one of the reasons listed in Table IT. Table

11

given Reasons

DISCONTINUATION

REASON 1OOmg

Unwanted Pregnancy Amenorrhea Prolonged Bleeding Irregular Bleeding Heavy Bleeding Spotting Other Medlcal Keasons Desires Pregnancy Other Non-Medical Reasons

All Discontinuations Lost to Follow-up End of study

DMPA

NUMBER OF WOMEN 150mg DMPA

2 33 40 15 17 5 24 11 56

0 60 39 14 6 9 20 6 48

203 45 361

202 48 357

TOTAL

2 93 79 29 23 14 44 17 104

(%I

(0.2) (7.6) (6.5) (2.4) (1.9) (1.2) (3.6) (1.4) (8.6)

405 (33.3) 93 (7.6) 718 (59.0) I

Table III gives the cumulative life-table discontinuation rates for each discontinuation reason by treatment group and centre, as well as those combined for all centres by each group. Large centre-to-centre

228

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1986 VOL.

34 NO. 3

46.0

2.3

0.0

0.0

1.4

0.0

0.0

31.3

6.4

0.0

0.0

0.0

1.2

2.0

3.3

tE4vYBLI;U)~

sKIITIlG

onust>ED1cu twisms

DtsIREsPHGWCY

UIHLHwr+xLxcAL tx?.Ems

um

ALLtcss!x?

.

14.9

1.3

6.0

lRRK.WWBmWG

To mImsIIp

1.2

0.0

PRo1MJ;EDULEEDrpc

26.8

3.9

4.3

1.1

0.0

0.0

.5.0

0.0

18.0 26.8

0.0

A'ENORKIW

0.0

KNIRUlI

Twelve-month KIN37Cxi

cumulative

4.0

10.2

1.3

23.4

11.2

10.4

0.0

4.1

52.0 61.2

8.2

3.0

0.0

43.0

1.8

1.6

2.5

8.7

6.4

0.0

13.5

16.3

9.6

0.0

14.7 20.1

6.7

23.8

6.0

0.0

0.0

0.0

0.0

0.0

3.5

5.5

16.9

7.2

9.3

20.3

2.0

0.0

1.7

1.9

3.5

0.0

0.0

0.0

0.0

0.0

0.0

1.7

0.0

1.8

1.9

1oang 15ang 1oang l5Ong 1OUng mng

m

III

0.0

1Oung lxhg

NWIWKIA

Table

UhuwltD PtuxNNJLY

.

0.0

0.0

6.4

0.0

56.6

14.8

3.4

64.2

13.2

0.0

16.2

10.0 19.9

3.1

3.0

12.8

19.7

4.0

20.4

0.0

22.0

0.0

loolilg mng

LJUUlJA%A

29.0

9.6

14.6

0.0

2.5

0.0

0.0

0.0

3.6

1.1

1.0

10%

32.0

12.7

14.7

0.0

5.2

0.0

0.0

46.0

7.2

5.0

9.0

10.1

0.0

6.5

44.9

0.5

7.0

5.4

6.4

0.0

2.5

40.7

8.2

11.1

2.5

5.1

1.1

3.4

3.3

1.4

2.8

0.0

7.7

10.7

i4.3

1.2

7.2

0.4

13.3

0.0

4.7

0.0

lmrg

41.2

8.6

9.9

1.3

4.3

1.. a

1.2

3.1

7.7

12.5

0.0

Is%

mcALFmJlATl~

2.4

0.0

sm

1oarig15%

rates

lmng

MNIlA

discontinuation

CONTRACEPTION

differences can be seen in reasons for dLscont_lrluatlon. rates for all reasons (including dlscontlnuation follow-up) by dosage group are shown in Figure 1.

The

women

cumulative

lost

to

were two pregnancies efficacy. There Contraceptive b) in a woman who attributable to method failure. One was In Kingston She was a conceived towards the end of the second lnjectlon interval. The 21-year-old woman with a parity of L and a Quetelet Index of 16.7. other was rn Manila in a woman who conceived towards the end of the first injection interval. She was a 22-year-old woman with a parity of Both women gave blrtn to normal 2 and a Quetelet Index of 21.3. healthy infants at term. The two pregnancies both occurred III the 1OOmg group, but there is The difference between the two groups. no statlstlcally slgnlficant corresponalng Pearl Index 1s 0.44 per 1OU woman-years (USUS confidence Llmlts, 0 to 0.92). Side Effects. A total of Y3 women dlscontlnued from the study cl because of lack of bleeding, whicn was interpreted by the physlclans as L 33 were recelvlng the LOOmg dose and 60 "amenorrhea". Of "hese women discontinuation rates at 12 months of the 15Omg dose, giving cumulaiive These rates are significantly different 7.22 and 12.5%, respectively. The cumulative dlscontlnuation rates for (X& = 8.28, P = 0.004). "amenorrhea" for each group by time are also shown in Figure 1.

The cumulative dlscontlnuatlon rates Figure 1. (including women lost to follow-up) and the cumulative rates for amenorrhea by dose of DMPA.

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for all reasons discontlnuatlon

1986 VOL.

34 NO. 3

CONTRACEPTION

A total of 77 women dlscontlnued for bleeding-related reasons Irregular bleeding or spotting) in the 1OOmg DMPA (heavy, prolonged, These correspond to cumulatrve and 68 In the 150mg group. group dlscontinuatxon rates at 12 months of 14.7% and 13.3%, respectively, and are not slgnifrcantly different (95% confidence limits for the There were also no difference in discontinuation rates, -2.8 to 5.7%). between of statlstlcally srgnificant differences the four categorres bleeding-related reasons. Tnere were no signrficant desire for pregnancy or other groups.

differences non-medical

in other reasons

medrcal between

reasons, the two

The cumulatrve drscontrnuation rates for all reasons (including women lost to follow-up) for each dosage group at 12 months are grven rn Figure 1. Tney are 40.7% and 41.2% for the 1UOmg and 150mg dose (95% confidence limits for the difference In groups, respectively dlscontrnuatron rates, -5.1 to 6.0%). Complaints At each of the four scheduled follow-up vlslts, women were asked by IndIrect questronlng to state any complarnts they consldered related Each woman could also attend the to metnod use since the last visrt. visits at which she could also cLlnlc at any time for unscheduled report ner complarnts. dare than half (58%) of the women reported no complalnts at their first follow-up visit whilst 26% reported bleeding 11% amenorrhea and 4% miscellaneous complalnts. problems, There was no By the difference observed between the two groups in these respects. time of tne fourth and final follow-up visit of the 718 women completing the study, 62% of the women were reporting no complaints, about lU% bleeding problems, 22% amenorrhea and 3/. miscellaneous There were no differences between the two groups at any of complaints. the scheduled follow-up visits. At the 65 unscheduled visits, 25% of the women registered no complaints, problems, 28% 40% bleeding amenorrhea and 8% other medical problems. Wergnt

Change

Tne rate of change in weignt every three months was calculated separately for those women having one, two, three or four scheduled follow-up vrsits and no statrstically significant dltferences were observed III these rates within or between dosage groups. The combined weight gain of all women in tne study was 0.37kg per three months, equivalent to L.48'kg per year (95% confidence limits, 1.29 to l.bbkg). A total of fourteen women gave weight gain due to method use as a reason for QlSCOntlnuatiOn. Of these, 8 women received 1OOmg DMPA and had a wergnt gain xr tne range of 2 to 8kg and b received 15Umg DMPA with weight gain from 4 to L3Kg. These women are included in Table 11 under other medrcal reasons.

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CONTRACEPTION

Blood

Pressure

Changes

There were no significant mean changes in either systolic or diastolic blood pressure within or between dosage groups. The combined mean change in systolic blood pressure was -O.lmmHg per year (95% confidence limits, -1 to 1mmHg) and for drastolic blood pressure 0.3mmHg per year (95% confidence limits, -0.3 to 0.9 mmHg). The protocol defined hypertension as a systolic blood pressure greater than 14OmmHg and/or a drastolic blood pressure greater than 90mmHg. There were three women inadvertently admitted into the study wrth hypertension (150/60, 130/100 and 14O/lOOmmHg) although this was an exclusion criterion. Two of these women became normotensive by the first follow-up visit and the third woman by the thrrd vrsit. Only three women were recommended to discontinue method use for hypertension during the course of the study. Two received 1OOmg DMPA and both had a systolic blood pressure of 16OmmHg at the first follow-up visit, whilst the third received 150mg and had a blood pressure of 160/115 at the second follow-up visit. A further 15 women had one measurement above the defined limits during the course of the study and 4 on more than but were not advised by the physician to discontinue one occasion, method use. There was no significant difference between the two dosage regimens in this respect. Vaginal

bleeding

analyses

Completed vaginal bleedrng record cards were obtained from the A subsequent paper will describe the women throughout the study. vagrnal bleeding patterns as determined by analysis of these records.

DISCUSSION

controlled This randomized, woman-years of method use with studied.

clinical the two

trial doses

provided of 100

a total of 912 and 150mg DMPA

with regard to contraceptive efficacy, no pregnancies due to method failure were reported in those women who received 150mg of There were two pregnancies, however, in the 1UOmg DMPA group DMPA. 100 women at 12 giving a cumulative life-table rate of 0.4% per months. Tnese results compare with a cumulative life-table rate of 0.1% (with 75% confidence limits, 0 to 0.3) in a group of women receiving 15Omg of DMPA in a previous Phase TIT clinical trial which included five of the seven centres participating in this study (2). Tne two pregnancies in the 1OOmg group occurred in two drfferent centres and did not give rise to a significantly different pregnancy rate from the 150mg group.

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1986 VOL. 34 NO. 3

CONTRACEPTION

In terms of overall discontinuation rates, including women lost to there was no difference between the two dosage regimens, follow-up, for the 150mg dose. The being 40.7% for the 1OOmg dose and 41.2% latter figure compares favourably with a previous Phase III clinical discontinuation rate of 51.4% with trial which showed a cumulative 150mg DMPA at 12 months (2). significantly for discontinuation tnat was only reason The two groups was "amenorrhea" with cumulative different between the discontinuation rates of 7.2% and 12.5% for the 1OOmg and 150mg groups, this difference between the groups is very much However, respectively. In Bangkok, Kingston and Manila, there centre-related (Table III). were only four women who discontinued for this reason, whilst in the Ljubljana and Szeged, 42, 20, Karachi, remaining centres, Alexandria, 14 and 13 subjects (a total of 89 women) discontinued, respectively. There were equal numbers of women discontinuing in each group in whilst the remaining three centres gave a total of 24 women Ljubljana, These three discontinuing on the 1OOmg regimen and 51 on the 150mg. centres each had a statistically significant excess of "amenorrhea" in the 15Omg group wnich underlines both the overall difference between as well as the need to undertake this type of the two dosage groups, settings. It must be emphasized clinical trial in various cultural as reported above, represents the women's tolerance that "amenorrhea", to lack of bleetiing rather tnan a standard clinical definition. centre Suggestions have been made as to reasons for such disparate culturally determined tolerance of These include differences (2). pregnant in the case of the fear of being menstrual disturbances, counselling given to the women by the clinic staff, as well amenorrhea, It is interesting to as tne staff's own attitudes towards the metnod. note tnat the two east Asian centres had an extremely low number of However, these two centres did have discontinuations for "amenorrhea". who women who were follow-up UT a greater number of lost to discontinued for non-medical reasons than the other centres, which may to the same phenomenon. The reflect different cultural expressions ascertained from the vaginal of vaginal bleeding patterns analysis bleeding diary records will address this issue in a subsequent paper. The cumulative discontinuation rate for "amenorrhea" of 12.5% with 150mg DMPA was comparable with previously reported results, such as in trial of DMPA and NET-EN noted above where the Phase III comparative the discontinuation rate was 11.9% at 12 months (2). The rate of 7.2% for the 1OOmg group is similar to a rate of 6.8% observed with 200mg NET-EN given every 60 days in the same study (2). related to disturbance of With regard to other reasons the menstrual bleeding, there was little difference between the two groups, discontinued for heavy bleeding in the although slightly more women 1OOmg than the 15Umg group. The numbers however are small, 17 and 6 there and are not statistically significant. respectively, Again, appear to be sajor between--centre differences.

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233

CONTRACEPTION

Women who are lost to follow-up often create a problem in large multicentred clinrcal trials since tne easiest way for a woman to drscontinue method use is by not returning to the clinic and berng difficult to trace. This is also a centre-related phenomenon, but overall there was no difference between groups 18.22 for the 1OOmg group and 8.6X for the 150mg group) or from the previously reported study on 150mg DMPA, which was 8.1X (2). Overall there 1s little difference between the two dosage regimens wrth regard to efficacy and side effects. However, while the pregnancy rate of observed rn the 0.4x 1OOmg group was not statistically srgnificant compared when with the reported 150mg two group, pregnancies did occur in women receiving the 1OOmg dose. It has been shown that MPA given intramuscularly 1s absorbed and/or metabolized more raprdly in drfferent population groups (5). Thus, further studres on the pharmacoklnetlcs of different formulations of DMPA in various populatron groups are being plannea by WHO's Task Force on Long-Acting Systemic Agents for Fertilrty Regulation address problems t0 the Until associated with bra-availability of tne drug in different women. these results are avarlable, it may be premature to reduce the dosage contraceptive formulatron and possrbly of this widely used, Long-acting rncrease the risk of pregnancy whrch may adversely affect women's acceptance of such a highly effective method.

ACKNOWLEDGEMENT

Tnis study was supported by WHO's Special Programme Development and Research Training in Human Reproduction.

of

Research,

REFERENCES

1.

World Organizatron, Special Programme of Research, Health Development and Research Training in Human Reproduction. Facts about inJectable contraceptrves: Memorandum from a WHO meeting. Bulletin of the World Health Organization 60: 199-210 (1982)

2.

World Healtn Organization, Special Development and Research Training Multinational comparatrve clrnical trial Norethisterone contraceptives: enantate regrmens and aepot-medroxyprogesterone Contraceptron, 28: l-20 (1983)

3.

World Health Organization, Special Programme of Research, Development and Research Training In Human Reproduction. DMPA and cancer: from a WHO meeting. Report Bulletrn of the World Health Crganrzation 64: 375-382 (1986)

234

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Research, Programme of in Human Reproduction. of long-acting injectable dosage given in two Final acetate. report.

1986 VOL. 34 NO. 3

CONTRACEPTION

i*.

Pardthalsung, 'I'.,Gray, K.H. and McDanLel, E. Return of fertility after dlscontinuatlon of depot-medroxyprogesterone acetate and intra-uterine devices in Northern Thailand. Lancet i: 509-511 (lYb0)

5.

Basso1 Fother~y,S~;.~r~f~~:,o,r~~;g,J~g~Cr~~~ot~~r~:~;;a~~~~~S~~he~~ar~~~ function following depot-medroxyprogesterone Fertlllty and Sterility

ZcetateS1n$~P*I 42: 21b-222 (1984)

administratlon at different

of doses.

6.

Fotherby, K., Koetsawang, S. and Mathrubutham, M. A pharmacoklnetic study of different doses of Depo-Provera. Contraception 22: 527-536 (1980)

7.

Life Farley, T.M.M. Statistics in Medicine

8.

ibkuch,

table methods for 5: 475-489 (1986)

R.W. and Simon evaluating a conservative 1037-1040 (1978)

contraceptive

research.

R.M. Sample size requirements therapy. Cancer Treatment Reports

SEPTEMBER 1986 VOL. 34 NO. 3

for 63:

235