Contraception with long-acting subdermal implants. A five-year clinical trial with silastic covered rod implants containing levonorgestrel

CONTRACEPTION

Contraception with Long-Acting Subdermal Implants. A Five-Year Contair,ing Levonorgestrel Clinical Trial With Silastic Covered Rod ImPlants The International

~~;;,~.

Committee fo: ContraeePtion the Pooulation Council

Fesearrh

i :f:??j of

Rob;;;;on",: ;;;;;q;eDiazb.

Francisco fAlvaree-Sancheiz. Elsimar Coutin$o-, Vivian S,rache Pavezb, Anibal Favndesii. Maria Lacarra , Maraarita e. croxatto a Roy’. Ana Rita da Silva . Irving Sivina anl Janet Stern

Pentt i

““$f;

‘+I ‘Consuitorio de Planificacion Familiar Sar!tia+go, IChile

aCenter for Biomedical Research The Population Council 1230 York Avenue New York, New York 10021 CSA

dMiddle SF49620

‘Asociacion Dominicana Fro Eienestar de la Familia. Inc. Santo Domingo, Dominican Republic eDepartment of Obstetrics and Gynecology California University of Southern School of Medicine 1240 North Mission Road California 90033 USA Los Angeles.

Finianc!

Jyvaskyla

Central Hoscital 62, Finland

f Maternilade Climerizb de oliveira Universidade Federal de 3ahia Salvador . Bahia. ..lEt-ai-’

gDepartmento de Tocoginecologie Facuitade de Ciencias Medicas de UNICAMF Rua Benjamin Constant 1657 Cx. Fostal li70. 13100 Campinas San Faulo. Brazil ab-tra-t c r.2 inPlants for A total of 189 women volunteered to accept subdermal The implants were “covered rods”, consisting of a .core contraception. by weight of levonorgestrel and polydiaethylrod containing equal parts tube of Silastic tubin:: with and sealed inside a thin-walled siloxane In one study 78 women used 4 3cm rods (study 07; and medical adhesive. In 5 years of use there were no in the other 111 women used 6 3cm rods. pregnancies in either group. Terminations because ,?f menstrual problems as frequent among the 4-rod users than among luser-s of the 6 were twice Menstrual pattern analysis is presented for the two rod regimens rods and wit the previously reported patterns for the 6-capsule compared ft !NORFLANT 1. release are regimen Long-term rates also m VI presented. Submitted for publication February 21, 1985 Accepted for publication March 20, 1985

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Introduction During the development of subdermal implant systems releasing progestins, implants delivering levonorgestrel were found to provide extremely effective protection against pregnancy in comparative trials system and the Copper T IU@ (TCu with another progestin implant 200) (1). This levonorgestrel system consists of six Silastic capsules It is currently being which deliver an average of about 30 ug per day. introduced for distribution under the tradename NORPLANTP. the PopulaCouncil’s trademark for contraceptive subdermal tion registered implants (2). other low-dose progestin-only dosage forms, the NoRp;;N;llmmon with implant system is associated with disruption of the menstrual cycle in many women (1). which resulted in a termination rate of 12.3 per 100 women at 12 months. Although this disruption has been reported to improve in 6 to 9 months (3) it was felt that continuation rates Previous work with would improve if this problem could be alleviated. “homogenous rods” containing levonorgestrel dispersed 258 by weight of that they exhibited higher release in polydimethylsiloxane had shown in higher blood levels of drug and a rates than capsules (41, resulting reduction in the number of bleeding days per “cycle” 15.6,7). AmenorThe rods were of low rhea was common among women using these implants. physical strength and fragmented easily when they were being removed. To improve the physical strength of the implants and to increase the release rate per implant, the “covered rod” was designed in which a core rod of equal weights of levonorgestrel and polydimethylsiloxane was the wall thicksealed inside Silastic medical grade bribing of one-half ness used for fabricating the NOPPLANT. capsules. Four 3 cm covered rods delivering a total of about 70 ug Per day The observed bleeding Patterns were used in the first trial (Study 07’). number of among women in this study were not as good as desired so the increased to six, delivering a total of about 105 ug per implants was day (Study 12). We now report

the

results

of these

Materials Admission

I. days

352

two trials

and Methods

Criteria

The study protocol required subjects To preclude enrollment of pregnant of the onset of menses.

to meet the criteria in women,admission was within

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1985 VOL. 3 1 NO. 4

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Table I. Criteria for Subject Selection Medical General L---& No Cardiovascular Problems Age 18-35 No Jaundice Not currently pregnant No Diabetes Not currently breast-feeding At least one menses postpartum No Pelvic Inflammatory Disease or post-abortion No Pathological Galactorrhea No Mental Illness or Used non-steroid contraception Depression continuously since last menses Reaularlv exposed to risk of ureanancv ._ ~ No Severe Varicosities No Frequent and Severe on implants Wirling to rely solely Headaches for contraception No Ectopic Pregnancy follow-up Accessible for regular No Depo-Provera since Last Pregnancy No Steroid Contraception within 45 Gravidity lt days Hemoglobin More than 10 g/100 ml Characteristics

of Subjects

Table II lists groups of women. higher among Study

of several characteristics the mean values For each characteristic, mean values 12 women than among women in Study 07. Table

II.

Characteristics Study

07.

Age School Years No. Live Births Height (cm) Weight (Kg) Systolic B.P. Diastolic B.P. Hemoglobin No. of Women Characteristics

of

of the two were slightly

of Subjects ’ aan values 4 Ros; 24.6 7.6 2.2 156 52.7 112.9 70.1 13.2 70

Study

12.

6 Rods 27.0 3.6 2. 3 159 57.6 116.9 70.9 13.4 111

Implants

Implants used in these studies were manufactured for the Population Council by Leiras Pharmaceuticals, Turku, Finland. The core rod containing equal parts by weight of micronized levonorgestrel and polydimethylsiloxane without filler was 3 cm in length and each rod was sealed inside a thin-walled medical grade Silastic Tube. The tube was sealed at each adhesive. Sets of either 4 or 6 end with 1 or 2 mm of medical implants were weighed to the nearest milligram, placed in serially numbered Tyvek pouches and the weight of each set was recorded on the label. The loss in weight while in situ could thus be determined by re-weighing each set on removal (8). All packages were sterilized with ethylene oxide in the pharmaceutical plant’s commercial sterilizer. Levonorgestrel Pennsylvania.

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was a gift Each implant

1985 VOL. 31 NO. 4

from used

Wyeth International, in study 07 contained

Philadelphia, 53.9 + 0.5

mg

353

CONTRACEPTION

(mean

t_ S.D.1

Protocol -.--__I____

of

of the

steroid

and

in

Study

12.

51.6

+ 1.2

mg (mean

+ SD.)

Stua

All women underwent a general physical and gynecological examination prior to placement of implants to exclude those who did not meet the admission criteria. Implants were placed under local anesthesia in either the palmar aspect of the forearm or the inner aspect of the upper arm (Finland) within 7 days of the onset of menses. Menstrual calendars were distributed and women were instructed to record all days of bleeding or spotting. Women were instructed to return to the clinic at 1 and after placement and every 3 months ther-eafter for the first 2 3 months years. Subsequent visits were made every 6 months. Women were encouraged to return to the clinic any time they had problems with the method or if they suspected were they pregnant. Implants could be removed at any time at the discretion of the doctor or on request by the subject. Originals of all Check Lists, Record forms were mailed to rates was performed as previously

Admissions, New York. described

Foliow Life-Table (91.

-Up and analysis

Bleeding of event

Result------e Net regimens. in Study

cumulative termination rates There were no pregnancies 07 and the 300 woman-years

are of

presented in Table III during the 170 woman-years use in Study 12.

for of

both use

Menstrual problems led to termination at more than twice the rate in Terminations for “Other Medical” in Study 12 Study 07 as in Study 12. Terminations were almost double those in Study 07. that could be attributed to effects of the steroid, such as headache. nervousness, nausea, were essentially the same, 12: in Study 07 and acne and hypertricosis The rest of the Other Medical was a miscellaneous lis: 14% in Study 12. The sum of terminations for menstrual problems and of minor comolaints. similar in both studies. Was very other medical problems The reasons for the differences in termination rates between the two to be related to najor differences in the kind of menregimens appears IV and V aspects of the bleeding In Tabies that occur. strual changes are compared wiCh those with the 4-and 6-crr,vered rod regimens patterns ! V that reported for the 6-capsule system i1.101. It is seen in Table dose of increased bleeding declined as the daily most indicators of The oniy e:icePtion numerous bleeding and steroid was increased. was which was experienced by imare than 31 days per interval) spotting days mar-e women at the intermediate dose level than by those either the at The 6-r.od regimen was associated with less higher or lower dose levels. bleeding than either of the other regimens.

354

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Table

III

Net Cumulative

Terminatiaon Study

07.

1 i

Study

Pregnancy Menst:ual Other Medical Personal Total Continuation No. Completing Year N=lll Acceptors Woman-Years of Use 300 -One clinic the number

terminated of subjects

Per

56, 3s

12,

6 Covered Years 1 2 I) 0 4 3 1’ 18 4’ 8 21 34 ?cI

66

87

62+

1

20

13 2: 58 42 7_;

Rods

2 0

f

3 21 17 46

13 22 ^ 2; 5?

54 43

1985 VOL.

0

47 35

in the second year which the study early by 16 in Study 07 and by 14 in Study 12.

Table V presents data on three measures of reduced infrequent bleeding, amenorrhea and three regimens. from 6 capsules Co 4 rods to As the dose was increased a progressive increase in the percentage of women parameters of decreased bleeding.

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and Year

, C

L

78 59

100 Women By Reason

Rods

-2

9 22

5

Continuat ion Year No. Completing N=?S Acceptors Women-Years of use 17@

4 Covere? Years ? l? 10 l? 44

@ 6

Pregnancy Problems Menstrual Other Med ical Personal Total

Pates

43 34

redilced

bleeding for the few bleedir,g
35.5

CONTRACEPTION

Table IV. Manifestations of Increased Bleeding of women experiencing four indicators of increased during successive 90-day intervals

Percent

Levocorqestrel

Implants

Frequent Bleeding (5+ runs:

Days l-90 91-iS0 131-270 271-360

6 Capsules 21 12 11 9

Prolonged Bleeding (St days a run)

l-90 91-180 181-275 271-360

35 27 2: 18

10 5 14 6

7 4 4 Fi

Numerous Bleeding Days (21 days)

l-90 91-180 181-270 271-360

27 23 18 16

19 162 9

6 3 c 0

Numerous Bleeding and Spotting Days (31t days)

l-90 91-180 181-270 271-360

36 21 15 12

39 45 25 23

75 S 2 0

in

Number of vaiid

Percent

Infrequent Bleeding (<2 runs)

cases

4 rods 6 2 2 4

l-90 91-180 181-270 271-360

Few Bleeding Days (‘5 days)

l-90 91-180 131-270 271-360

(1; cm) (70) !62j !5?! 152j

6 pods 2 3 2 0

(1% cm) ‘95.) (?4l (49) 124j

in interval

Table V. Manifestations of Pedilced of women experiencing khree indicators Levonorgestrel 6 capsules (19 cmj 4 rods Days l-90 14 91-130 19 181-270 1: 271-360 10

Amenorrhea (60+ days without bleeding)

356

(lScm!

bleeding

Pleeding of reduce? bleeding Implant (12 cm! 6 rods (1S cm) 21 59 37 94 3? 30 44 92

26 24

39 42 42 42

66 82 SS 92

16 14 13 9

23 31 39 29

61 79 76

32 33

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>8:#5p

____L._.

aac,es _..

4s implant; were removed +_hey were rent to C.‘ie New ‘fork la?orztories ana:ysie b ‘y me t .YDC5 p r e v i r)I:s 1 ‘y Fcpula’_icn C,D,ZCi 1 for of the lost dpsrribed ie;. of levGri2rgestrei Fig. 1 is a plot of milligrams from a single 3 cm covered rod *vs. time. ‘Tt‘e polr,ts were calculated by dividing the tr,tal loss in weight from a set by ei!!>ur e_he 4 c,r 6, number of implant; in a particiilar set. Table VI com;la:e; release rate estimates for the rad reg;mens with the rate for the ;i:c-capsule system repor’Ied by Diaz et A& (3) __ Table

VI.

Daily

Dose :f

Zegimcn

Dose,

Levonorgestre! ~;g ;er

6-capsule 4-rod C-rod

COVERED 40_

Per

II) ?2 105

RODS:

3cm

Rod:

-

RELEASE

Study

82-2200 30

2a;r

OF

LEVONORGESTREL

07612

day&

n-68 slope=0.0158 r-0.987

0

L

1

I

I

1

I

1

1

I

2

4

6

8

10

12

14

18

18

HUNDREDS

Fig. 1: Release grams v5 time.

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1 20

1 22

OF DAYS

from a ;in?le

3 rm

COwred

rod,

1n

357

milli-

CONTRACEPTION

Discussiqn The objective of reducing the termination r-ates for menstrual pro?lems of 12.3 per 100 women in the first year of use among NOP.P!_ANTRcapF I r s f_ 1,e e is?ile users by increasing the dose was moderately sucressful. termination rates for the 4-covered rsd and 6-covered rod regimens were +brc,!“i 8 and 4 per 100 wn,men. respectively. For rhe second _*1.“-3.. f 0 lur t 5 years of use,menstrual problem Cermina:icn rates were over twice as high for the 4-rod users as for the 6-rod users. This appeir: to be as;,ocated with a hicgher oercentage of women who experienced more than 31 days of bleeding and spotting while Iusing the 4 rods than while musing the 6 rods because all other parameters showed reductior. in bleeding. These data indicate that women fc,lerate reduced bleeding and even frank amenorrhea better than increased bieeding and particularly a high number of bleeding plus spot’_ing days. The $-year cum~ulat’ve 1 termin?-tion wi’_h the 4-covered rod regimen is 1D rate for menstrual problems points higher than that reported by Sivin & al_ for a 4 -year ca-,snle study where 3 of the clinics studv 12;. were the same ones as in this The reduction in termination rates for menstrual problems in users of the 6-rod regimens was offset by terminations for otter medical reasame First year sclns and the net result was about the c 0n t i n U a t i 0 n rates both regimens were about the same as previously reported for fffr NOR.PLANT caps?lles ( 1). At the end of 6 years (22DO days! there is still 33: of the initial sternid content in the rods and there is nc, evidence for a in the rate of disappearance of drug from the rods. One could then select the desired dose of levonorgestrel, adjust the number of centimeters of covered rod to deliver that dose and have considerable confidence that it will be delivered for at least 5 years.
Acknowledgement ____._--.. _.. This work was undertaken as part of the contraceptive developmen? program sponsored and coordinated by the International Committee for New York, New Contraception Research of the Population Council, Inc., York. The financial support provided by the International Development Research Centre of Canada, the U.S. Agency for International Development the Rockefeller Foundation, (Grant AID/pha 11161, the Ford Foundation, Hecht Fund is gratefully a c i:-. the Mellon Foundation and the Geo. J. reflect the policy’of any nowledged. The content doe: not necessarily of the funding sources References -.___-__ 1.

I..

7L.

Special

3.

Diaz,

358

ICCR Contraception Issue S..

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M., Miranda,

Planning P.,

14: 159-193.1933.

Robertson,

D

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N , Sivin.

I..

and

1985 VOL. 31 NO. 4

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Croxatto, Silastic

H.B. Implants

A Five -)$,ar (NORPLANT ?.

Clinical Trial of Levonorgestrel Con’raception ?5:447-456.1FB2.

4.

Nash, H.A.. Robertson, Steroid Release from 19:367-384.1Y73.

5.

Faundes, F. First subdermal

6.

F., Mishell. D.R.. Lumkin, El.. and Gentzschein. Roy, S., Stanczyk, E. Clinical and Ecdocrinological Study of Continuous Levonorgestrel Administration from Subcutaneous Solid Polydimethylsiloxane Rods. Contraception 21:585-615,lYBO.

7.

Weiner, Silastic Ovarian

8.

Robertson. D.N.. Sivin, I., Nash, Release Rates of Levonorgestrel in genous Rods and covered Rods 495.1983.

9.

Jain. A. and Sivin, Recommendations.

10.

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D.N.. Moo-Young. A.J., and Atkinson. L E. Silastic Capsules and Rods. Contraception

A., Mejias. V.B.. DeLeon, P.. Robertson, D.. and Alvarez, year clinical experience with six levonorgestrel rods as Contraception ?C:16?-175.1979. contraception.

E.D.B. Contraception with d-Norgest:el E. and Johansson, Rods: Plasma Levels of d-Norgestrel and Influence on the Function. Contraception 14:55!-56?.1Y76.

I. Life-Table Analysis of IUDs. Problems Studies in Famiiy Planning @ No. ?:lY77.

Faundes. A. , Sivin, I.. and Stern, Implants, An Analysis of Menstrilal tion !8:355-365.1978.

1985 VOL.

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and H.A., Braun. J. Dinh. J. from SilasticR Capsules. HomoHumans. Contraception ?7:483-

J. Long -Acting Bleeding Patterns.

and

Contraceptive Contracep-

359