Clinical trial with subdermal implants containing norgestrienone

CONTRACEPTION

CLINICAL TRIAL WITH SUBDERMAL IMPLANTS CONTAINING NORGESTRIENONE

S. Diaz*, M. Paves*, E. Quinteros*, J. Diaz**, D.N. Robertson*** and H.B. Croxatto*

*

Consultorio de Planificacion Familiar, Lastarria 29, Depto. 101, Santiago, Chile

**

Servicio de Obstetricia y Ginecologia, Hospital Sotero de1 Rio, Puente Alto, Chile

***

The Population Council, The Rockefeller University, New York, N.Y., U.S.A.

ABSTRACT Norgestrienone implants delivering approximately 225 l.rg/day were tested clinically for contraceptive effectiveness and acceptability in 145 women. Five pregnancies occurred in 2259 woman-months of use, one in the 11th month, one in the 15th and three in the 16th month of use. Continuation rate at 12 months was 86.7. The number of bleeding runs and bleeding days was increased in approximately 12% of the subjects. Ten percent of the patients had no bleeding in the first 90 days of treatment. Changes in bleeding pattern led to closures in four cases. Headache and signs of mild androgenicity were among the leading side effects. Blood and urine analysis throughout the study showed normal values of 17 different parameters, but a tendency to lower cholesterolemia not associated with changes in thyroid hormone levels, was observed in several patients. Cortisol was found slightly under the lower normal range in one subject without clinical manifestations of hypoadrenalism. It is concluded that norgestrienone implants should be replaced every twelve months for maximal contraceptive effect and because of their efficacy and good acceptability, evaluation of their long term use is warranted.

Accepted

OCTOBER

for

publication

1978 VOL. 18 NO. 4

September

1, 1978

429

CONTRACEPTION Introduction

The contraceptive action of norgestrienone subdermal implants in women was first reported by Coutinho and Da Silva (1). Using from 1 to 4 capsules, they showed a dose related effectiveness which lasted for at least one year with the higher dose. Most women continued to bleed regularly but episodes of amenorrhea as well as breakthrough bleeding were reported by some. Their results encouraged the present study in which six capsules were tested for use effectiveness and acceptability in Chilean women.

Material and Methods

One-hundred-and-forty-seven women were admitted to the study. At the time of admission, they were either menstruating regularly or had had their first post-partum or post-abortum menses. One patient was partially lactating. Women using IUDs had the device removed with their last menses. With the exception of 9 cases, all women using hormonal contraceptives stopped treatment at least 60 days prior to the insertion of the implants. None had received injectable contraceptives after their last delivery or abortion. All subjects were instructed to use no other means of protection to avoid pregnancy during the study. The age range was 17 to 36 years with a mean of 25.7. The number of previous pregnancies ranged from 1 to 10 with a mean of 3.3. One subject was found to have been pregnant on admission and one subject was found to have had an IUD in place during the course of the study. These subjects were excluded from the analysis of results. Two subjects at Sotero de1 Rio Hospital expelled one implant each one week after placement but this was not known until 18 months later when they returned for removal and replacement when only 5 implants were found. Questioning of the subjects elicited the expulsion information. Although it is thought that the expulsions were related to the technique of insertion,they are included in the analysis of the data because expulsion could be a part of the method. Implants used in this study were manufactured for The Population Council by Laboratorios Gutfol, S.A., Mexico City (Lot No. 030974). Implants were prepared by packing norgestrienone crystals into SilasticR* tubing of 2.41 mm outside diameter,1.57 mm inside diameter and 0.42 mm wall thickness. The filled part was 30 mm and the total length 34 mm. Two mm at each end were used to close the tubing with

* SilasticR is the Registered Trademark for Dow Corning Corporation's brand of polydimethylsiloxane.

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SilasticR Medical Adhesive, Silicone type A. Norgestrienone (R 2010 = 17 alpha-ethynyl-17 hydroxy-estra-4, 9, 11-triene-3-one) was a gift from Roussel UCLAF, Paris, France. The total amount of steroid in each implant was 31.5 f 1.1 mg (mean f S.D.). Implants were sterilized by exposure to ethylene oxide. Release

rate

in a one year -in vitro

incubation

was

15-18

Kg/cm/day.

Six capsules were inserted in each patient within the first week of the cycle. They were inserted under the skin of the volar aspect of the forearm through an ll-gauge trocar after local anesthesia with lidocaine 2%. Before initiating treatment, all women had a general including-measurement of the physical and gynecological examination, breasts (2) and a Pap smear. Menstrual calendar cards were distributed Analysis of menstrual pattern was to record all vaginal bleedings. done according to Rodriguez _et al. (3) and only patients having no hormonal treatment for at least 90 days prior to the study and having Sixty-one complete bleeding records were included in this analysis. patients met these conditions. Treatment of bleeding irregularities in this group was limited to methyl ergonovine, which was given once in Control visits were scheduled three cases, to stop prolonged bleeding. at the first month after placement of the implant and every three months At each visit, physical and gynecological examinations thereafter. were performed and symptoms and bleeding episodes were recorded. symptoms were investigated following a questionnaire. A pregnancy test in urine SMA 12a (excluding lactic was done 15 to 20 days after menses delay. dehydrogenase), cortisol, blood cell count, plasma protein electrophoresis, urine analysis, oral glucose tolerance test, T3 and T4 were done before treatment and repeated in the same patients at 3, 6, 9, and 12 months The number of patients submitted to each test is shown of treatment. in Table I. Table Blood

and Urine Analysis

Test SMA 12a Blood cell count Urine analysis Plasma protein electrophoresis Glucose tolerance Cortisol T3 T4

a.

-

I

17 14 16 16 13 11 10 11

urea nitrogen, uric acid, cholesterol, total protein, Glucose, albumin, transaminases (SGOT and SGPT), alkaline phosphatase, calcium and total bilirubin. inorganic phosphorus,

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Treatment was terminated by removing the implants through a 5 mm skin incision under local anesthesia. The amount of steroid remaining in each capsule was determined by U.V. absorption spectrometry as previously described (2). From these data and the initial content of the capsules, the average release rate _in vivo was calculated. Results

Five pregnancies occurred in 2259 woman-months of use: one in the 11th month, one in the 15th and 3 in the 16th. Three pregnancies terminated at 9 months with the delivery of a normal child. One was terminated by induced abortion and one was lost to follow-up. Termination rates up to 12 months are shown in Table II. Table II Net Cumulative Termination and Continuation Rates

Pregnancy Bleeding Other Medical Planning Pregnancy Other Personal Totals Continuation Rate

O-6 0 0 3 0 3 6

Rate 6 MO 0 0 2.1 0 2.1 4.2

7-12 1 4 5 1 2 13

Rate 7-12 MO 0.7 2.8 3.5 0.7 1.4

Cumulative Rate 12 MO

9.1

13.3

95.8

0.7 2.8 5.6 0.7 3.5

86.7

Terminations for bleeding took place only between 6 and 12 months, three for excessive bleeding and one for amenorrhea. The main reasons for removal were "other medical" and "other personal". Other medical reasons are detailed in Table III.

Table III Closures for Other Medical Reasons Reason

Number of subjects

Headache Jaundice Chloasma Acne + hyperthricosis Ovarian cyst Calactorrhea

3 1 1 1 1 1 8

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CONTRACEPTION

The continuation rate at the end of one year was 86.7. Because effectiveness of an implant is necessarily dependent on time of use, it is important to determine when it should be renewed for optimal safety. Analysis of gross cumulative pregnancy rates can provide this information, which is shown in Table IV. Table IV Cumulative Gross Pregnancy Rates Month

Rate, %

0.80

11 15 16

1.84 5.61

After the 15th month of use there appeared to be a rapid decline in effectiveness, which led the investigators to remove the implants in the remaining patients as they completed 14 months of treatment. Side effects are listed in Table V. Table V Side Effects Symptoms or Pindings Headache Enlarged adnexa Hyperthricosis Acne Breast hypotrophya Mastalgia Nervousness Lower abdominal pain Pruritus Dizziness Chloasma Hematic colostrum Increased varicosities Jaundice

% Women 28.5 14.6 7.8 6.3 6.3 4.9 4.9 3.5 2.8 0.7 0.7 0.7 0.7 0.7

Symptoms were included if they were reported during at least two follow-up visits and they had changed significantly from the pretreatment period. Headache was the most common complaint, Enlarged adnexa were interpreted as ovarian cyst and they usually showed spontaneous remission within a few days. One case was submitted to diagnostic laparotomy and a follicular cyst with a diameterof 6 cm was removed. Breast hypotrophya was listed when breast measurements decreased at least 4 cm and was not associated with weight loss. Hematic colostrum was found in one patient upon compression of the nipple. The implants were removed and the patient was sent to the pathology department where malignancy was excluded.

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Intercurrent diseases during treatment included gall bladder disease, which has a high prevalence among Chilean women (4). Biliary colic was reported by 5 women and led to surgical treatment in 2 of them. Mild hypertension was detected in 2 cases, viral hepatitis developed in one case and one episode of hemoptysis due to bronchiectasia occurred in another patient. The effect of treatment upon bleeding pattern was assessed taking into account the number of bleeding runs, the number of bleeding days and the average episode length in the first and third ninety-day period of treatment. The number of bleeding runs is shown in Fig. 1. Amenorrhea developed in 8.2% of subjects in the first period and a number of bleeding runs in excess of 5 occurred in 3.3% of subjects during the first period. The proportion of subjects who fell in the range of 2 to 5 was 83.6%. During the third period, all subjects had between 1 and 5 bleeding runs and 92% had between 2 and 5. The number of bleeding days is shown in Fig. 2. A wide variation from 0 to more than 28 days was observed in the first period, with negligible changes in the third period. Patients having more than 20 days of bleeding per 90 days were 10 and 12% in the first and third periods,respectively. The average episode length is shown in Fig. 3. The proportion of subjects in the range of 21 to 42 days were 65.6% in the first period and 72.0% in the third. The results of clinical chemistry showed values fluctuating within the normal range in all patients examined for all tests indicated Lr Table I, with the exception of plasma cholesterol and cortisol. Average plasma cholesterol levels at 3, 9 and 12 months were lower The difference between than pretreatment values, as shown in Fig. 4. pretreatment and treatment values was statistically significant. Average cortisol levels fluctuated within the normal range with In one patient, cortisol a tendency to decrease after the sixth month. values of 10.6 and 11.25 bg/lOO ml were found at 9 and 12 months of This is slightly under 12 yg/lOO ml, the treatment, respectively. lower limit of the local normal range.

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CONTRACEPTION

30

: g

20

k t =

10

K P

m

0 1

0

2

3

4

5

6

I

3

4

5

6

7

6

9

10

B

9

10

B

30

20

10

0

I -:

0

1

2

NUMBER

OF BLEEDING

RUNS

Figure 1 - Percent distribution of women according to number of bleeding runs in a period of 90 days. A = first period; B = third period.

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CONTRACEPTION

z 20

Y g

1A

k 10

Figure 2 - Percent distribution of women according to number of bleeding days in a period of 90 days. A = first ninety days of treatment; B = third 90 days of treatment.

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OCTOBER 1978VOL. 18 NO. 4

CONTRACEPTION

40 A

5 I

30-

P g

20.

s 8 %

10 -

0 i

AVERAGE

EPISOCE

LENGTH

Figure 3 - Percent distribution of women according to average episode length. A = average duration of episodes initiated in the first 90 days of treatment; B = episodes initiated in the third 90 days of treatment.

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CONTRACEPTION

NORGESTRIENONE

IMPLANTS

I

mean: 5.4

ISO-

0

9

3 Month

of

12

treatment

Figure4 - Serum cholesterol levels in women treated with norgestrienone implants. Each point is the mean for the number of subjects indicated between parenthesis. p values at 3, 9 and 12 months vs beginning of treatment (Student's test).

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OCTOBER

1978VOL.18N0.4

CONTRACEPTION

were

The average release rate of norgestrienone in -- situ is shown in Table VI.

over

the period

the implants

Table VI

Rate of Release of Norgestrienone from Silastic Implanted Subdermally in Women Days -in situ

Number of capsules analyzed

Capsules

Release rate &cm/day Mean f S.D.

251 351 451 551

-

12 18 52 28

350 450 550 650

Calculated average release rates in pregnant subjects was not different.

13.09 f 1.36 12.96 f 0.68 11.84 f 0.76 11.78 l 0.79

and non-pregnant

Discussion

The present results are in general agreement with a previous report on contraceptive efficacy and bleeding pattern associated with norgestrienone implants (1). The continuation rate at 12 months was comparable to that of the best reversible methods presently available. Bleeding irregularities were well tolerated and contributed to the total number of closures in a very small proportion. Partial loss of contraceptive effectiveness somewhere between 12 and 15 months of use gave an indication that treatment with these implants should allow for replacement at yearly intervals, for maximal safety. Most implants removed after one year still contained nearly 50% of their initial steroid load but only about 35% after 16 months. Loss of efficacy was not due to degradation of the drug caused by long term residence of the capsules -in viva. The steroid recoveredfrom a set of implants that had been in one subject for 18 months was shown to be identical to a reference standard by melting point, mixed melting point and spectrophotometric analysis. Since diffusion from the capsules depends on the ability of the drug to dissolve in the silicone rubber and contact of the crystals of the drug with the inside walls of the capsules is necessary to effect this process, the decreasing contraceptive efficacy with time is undoubtedly due to partial loss of contact of the drug with the walls of the capsule as the reservoir is depleted, as shown by Nash Ed &. (5). Good acceptability of these implants is reflected in the continuation rates at 12 and 15 months. Side effects attributable to the method were limited to common complaints associated with the use of hormonal contraceptives and intercurrent diseases were those which have high

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CONTRACEPTION

prevalence in our population. The tendency for decreased cholesterol levels in plasma is in itself of no concern, but its full significance cannot be assessed until the entire spectrum of lipids and lipoprotein changes is explored. Alterations in cortisol levels in one patient were marginal and devoid of clinical manifestations. Considering the effectiveness and general good acceptability of these implants, it is concluded that, even if their life span is restricted to 12 - 15 months, further evaluation of their long term use is warranted.

Acknowledgement This work was undertaken as part of the contraceptive development research program sponsored and coordinated by the International Committee for Contraception Research of The Population Council, Inc., New York, N.Y.

References 1.

Coutinho, E.M. and Da Silva, A.R., One year contraception with norgestrienone subdermal silastic implants. Fertil. Steril. 25: 170, (1974).

2.

Diaz, S., Pavez, M., Quinteros, E., Robertson, D.N. and Croxatto, H.B., Clinical trial with subdermal implants of the progestin R 2323. Contraception 16: 155 (1977).

3.

Rodriguez, G., Faundes, A.L. and Atkinson, L.E., Enfoque al analisis de patrones menstruales en la evaluaxion critica de anticonceptivos. Estudios de Poblacion 1:90, (1976).

4.

Marinovic, I., Guerra, C. and Larach, G., Incidencia de litiasis biliar en material de autopsias y analisis de la composition de 10s calculos. Rev. Med. Chile 100: 1320, (1972).

5.

Nash, H.A., Robertson, D.N., Moo Young, A.J. and Atkinson, L.E., Steroid release from silastic capsules and rods. Contraception, this issue.

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1978 VOL. 18 NO. 4