- Email: [email protected]
Evaluation of the clinical performance of three triphasic oral contraceptives: A multicenter, randomized comparative trial
GOldzieher
terindividual variation, the clinician may well improve the efficacy/cycle controll side effects profile experienced by the patients. When it comes to variations in multinational trial data, significant qualitative differences in contraceptive steroid metabolism among geographic areas may yield discrepancies unrelated to experimental design. To reach clinical judgments, the practitioner should probably weigh most heavily the findings derived from populations most similar to his/her own. REFERENCES 1. Back DJ, Bates M, Breckenridge AM, et al. The pharmacokinetics of levonorgestrel and ethynyl estradiol in women-studies with Ovran and Ovranette. Contraception 1981 ;23:229-39. 2. Newburger J, Goldzieher JW. Pharmacokinetics of ethynyl estradiol: a current view. Contraception 1985;32:3344. 3. Nilsson S, Nygren KG. Ethinyl estradiol in peripheral plasma after oral administration of 30 fLg and 50 fLg to women. Contraception 1978; 18:469-75.
May 1989 Am J Obstet Gynecol
4. Back DJ, Bolt HM, Breckenridge AM, et al. The pharmacokinetics of a large (3 mg) oral dose of ethynyl estradiol in women. Contraception 1980;21: 145-53. 5. Back DJ, Breckenridge AM, Crawford FE, et al. An investigation of the pharmacokinetics of ethynyl estradiol in women using radioimmunoassay. Contraception 1979; 20:263-73. 6. Humpel M, Wendt G, Pommerenke G, et al. Investigations of pharmacokinetics of leveonorgestrel to specific consideration of a possible first-pass effect in women. Contraception 1978; 17:207-20. 7. Back DJ, Breckenridge AM, Crawford FE, et al. Kinetics of norethindrone in women II: single-dose kinetics. Clin Pharmacol Ther 1978;24:448-53. 8. Back DJ, Breckenridge AM, Crawford FE, et al. Kinetics of norethindrone in women I: radioimmunoassay and concentrations during multiple dosing. Clin Pharmacol Ther 1978;24. 9. Okerholm RA, Peterson FE, Keeley FJ, et al. Bioavailability of norethindrone in human subjects. Eur J Clin Pharmacol 1978; 13:35-9. 10. Orme ML'E, Back DJ, Breckenridge AM. Clinical pharmacokinetics of oral contraceptive steroids. Clin Pharmacokinet 1983;8:95.
Evaluation of the clinical performance of three triphasic oral contraceptives: A multicenter, randomized comparative trial Lee H. Schilling, MD: O. Thomas Bolding, MD: C. Brandon Chenault, MD; Augusto P. Chong, MD/ Fred Fleury, MD: Katherine Forrest, MD,' Henry I. Glick, MD,g H. M. Hasson, MD: Charles G. Heil, MD,; and Robert S. London, MDj Fresno, California, Birmingham, Alabama, San Antonio, Texas, Hartford, Connecticut, Springfield, Illinois, San Jose, California, Miami, Florida, Chicago, Illinois, Upper Darby, Pennsylvania, and Baltimore, Maryland Three hundred thirteen women partiCipated in an open, multicenter comparison of the incidence of intermenstrual bleeding (breakthrough bleeding and or spotting) assOCiated with the use of three triphasic oral contraceptives. Triphasil (n = 107), containing levonorgestrel and ethinyl estradiol, and Ortho-Novum 71717 (n = 97) and Tri-Norinyl (n = 109), both of which contain norethindrone and ethinyl estradiol, were administered over four cycles for a total of 1141 cycles. The total incidence of intermenstrual bleeding was significantly lower with Triphasil (17.2%) than with Ortho-Novum 71717 (39.5%) or Tri-Norinyl (49.0%). The pattern remained the same when findings were analyzed cycle by cycle and for breakthrough bleeding and spotting separately. The incidence of other side effects was comparable for all regimens. Results of this study demonstrate supenor cycle control with Triphasil compared with Ortho-Novum 71717 and Tri-Norinyl during the first four cycles of use. (AM J OBSTET GVNECOL 1989;160:1264-8.)
Key words: Breakthrough bleeding, intermenstrual bleeding, levonorgestrel, norethindrone, spotting, triphasic oral contraceptives
From Student Health Services," California State University-Fresno, the Brookwood Medical Center.' A Woman's ChOIce,' Mount Sinai Hospital/ the Southern Illznois School of Medlczne: the Planned Parenthood ASSOCIation of Santa Clara County, Inc.,! the Baptist Hospital of Miami,' the ObstetrzcslGynecology Climc, Grant Hos-
1264
pltal.' the Fitzgerald Mercy Hospital,' and the DIVISIOn of ReproductIVe Medlczne,' North Charle5 General Hospital. Reprznt requests: Lee H. Schilling, MD, Student Health SerVices, California State UnIVerSity-Fresno, Fresno, CA 937400081.
Evaluation of three triphasic oral contraceptives
Volume 160 Number 5, Part 2
In the years since the introduction of oral contraceptives, recognition of dose-related cardiovascular and metabolic side effects has led to the development of new dosage forms with reduced steroid content.'-6 At the lowest dose levels necessary to minimize the risks of biochemical alterations, endometrial support may be changed, resulting in an increase in the incidence of intermenstrual bleeding,7 In an attempt to further reduce steroid dose and maintain endometrial integrity, a new approach to oral contraceptive dosing was introduced. Instead of containing fixed ratios of steroid, these new oral contraceptives alter the level of estrogen and/ or progestin in three different phases during the month. Despite hormonal content even lower than that of most low-dose monophasic oral contraceptives, the triphasics have uniformly been claimed to produce a low incidence of bleeding irregularities, even though there is a great variability in the steroidal content and design of each pill." H Y Of the three triphasic formulations available, one uses levonorgestrel as the progestin component, whereas the other two use norethindrone. In one, both hormone levels are varied, whereas in the other two, only the progestin content is altered. To evaluate bleeding patterns associated with individual triphasic formulations, a multicenter, randomized clinical study was undertaken to compare Triphasil (Wyeth-Ayerst Laboratories, Philadelphia, Pa.), containing levonorgestrel and ethinyl estradiol, and Ortho-Novum 717 /7 (Ortho Pharmaceuticals, Raritan, N.J.) and Tri-Norinyl (Syntex Laboratories, Palo Alto, Calif.), both of which contain norethindrone and ethinyl estradiol. The study encompassed the critical first four cycles of use. Material and methods
From 1986 through 1987, healthy, sexually active, female volunteers, between 18 and 37 years of age, were enrolled and treated at JO sites: California (two), Alabama, Florida, Illinois (two), Texas, Maryland, Pennsylvania, and Connecticut. All investigations were approved by the appropriate institutional review boards. After counseling, each volunteer gave informed consent and was screened for contraindications to the use of oral contraceptives. Only subjects who had not used reproductive hormones for at least 1 month and who had no history of irregular menses, amenorrhea, or intermenstrual bleeding within 6 months of enrollment were included. A medical and gynecologic history, including smoking, alcohol use, and dietary habits, was taken, and a physical examination with emphasis on breast and pelvic regions was performed. Weight and blood pressure were recorded at followup visits. Routine laboratory chemistries and Papanicolaou smears were obtained. Normal findings were
1265
Table I. Patient demographics
Total
No.
Age (yr) Mean Range Age (yr) <20 20-24 25-29 ~30
Race White Black Other
Tnphasil
Ortho-Novum 71717
Tn-Nonnyl
107
97
109
23.9 18-35
23.9 18-36
24.3 18-37
14% 52% 20% 14%
19% 42% 26% 13%
16% 44% 26% 15%
74% 12% 14%
76% 9% 14%
69% 17% 15%
required for inclusion in the study. Use of certain medications, such as antibiotics, anticoagulants, aspirin or aspirin-containing medications, isotretinoin, or sedatives, within 14 days of the start of the study or at any time during the study, was prohibited. Screened subjects were randomly assigned to one of the three triphasic oral contraceptives: Triphasil (n = 107), Ortho-Novum 717/7 (n = 97), and TriNorinyl (n = 109) (Table I). Each subject maintained a daily diary card to record pills taken, menstrual and intermenstrual bleeding, symptoms and complaints, and any other medications used. Follow-up visits were scheduled after the first and last treatment cycles. The treatment regimens (Table II) consisted of 21 active tablets, followed by seven inert tablets. Triphasil was started on the first day of bleeding, whereas the other two contraceptives were started on the first Sunday after the onset of bleeding, as directed in each manufacturer's package insert. Thereafter, tablets from each package of pills were taken serially for 28 days. The incidence of intermenstrual bleeding, breakthrough bleeding, spotting, and amenorrhea during treatment was compared among groups by means of Fisher's exact test. Results
A total of 313 subjects participated in at least one cycle of treatment for an overall total of 1141 cycles for all regimens. The number of subjects per cycle is shown in Table III. During treatment, cycle length was similar for each regimen (27.2 to 28.1 days). Length of menses was also similar (4.4 to 4.7 days). Latent period before onset of withdrawal bleeding ranged from l.1 to 2.3 days. To eliminate possible bias arising from the difference in starting day (day I for Triphasil and the first Sunday after onset of menses for Ortho-Novum 7/717 and TriNorinyl), bleeding data were analyzed both with and without the first 7 days of pill consumption during cycle
1266 Schilling et al.
Am
May 1989
J Obstet Gynecol
Table II. Hormonal content of three triphasic regimens Progestm
Regimen
Triphasil Phase 1 Phase 2 Phase 3 Ortho-Novum 7/7/7 Phase 1 Phase 2 Phase 3 Tri-Norinyl Phase 1 Phase 2 Phase 3
Levonorgestrel Levonorgestrel Levonorgestrel
50 75 125
Ethinyl estradiol Ethinyl estradiol Ethinyl estradiol
30 40 30
6 5 10
Norethindrone Norethindrone Norethindrone
500 750 1,000
Ethinyl estradiol Ethinyl estradiol Ethinyl estradiol
35 35 35
7 7 7
Norethindrone Norethindrone Norethindrone
500 1,000 500
Ethinyl estradiol Ethinyl estradiol Ethinyl estradiol
35 35 35
7 9 5
Table III. Study population
Table V. Total incidence of spotting by individual and total cycles
Ortho-Novum
71717
Tnphasil (%)
Total cycles Total woman-years Total subjects Cycle 1 Cycle 2 Cycle 3 Cycle 4
Tn-Nonnyl (%)
(%)
389 29.9
352 27.1
107 107 100 93 89
No. of days
Estrogen
J.Lg
400 30.8 109 109 105 97 89
97 97 92 83 80
Tnphaszl (%)
Cycle 1 Cycle 2 Cycle 3 Cycle 4 Total cycles
OrtilO-Novum
71717
17.8 14.0 17.2 10.1 14.9
(%)
Tn-Norinyl (%)
48.5* 34.8* 28.9 25.0t 34.9
56.9* 34.3t 30.9* 39.3* 40.8
*Versus Triphasil, p < 0.001. tVersus Triphasil, p < 0.0 I. tVersus Triphasil. p < 0.05.
Table IV. Total incidence of breakthrough bleeding by individual and total cycles Ortho-Novum
Cycle 1 Cycle 2 Cycle 3 Cycle 4 Total cycles
Table VI. Total incidence of intermenstrual bleeding by individual and total cycles
TriPhasil (%)
71717 (%)
Tn-Norinyl (%)
6.5 10.0 11.8 6.7 8.7
29.9* 26.1t 20.5 17.5* 23.9
39.4* 28.6* 24.7* 20.2* 28.8
*Versus Triphasil, p < 0.001. tVersus Triphasil, p < 0.01. *Versus Triphasil, p < 0.05.
1. No difference was found to result from the dissimilar starting days. The total incidence of breakthrough bleeding, defined as bleeding requiring sanitary protection, was different for each of the triphasic regimens (Table IV). Compared with Triphasil, the rate of bleeding with TriNorinyl was almost three times greater and with OrthoNovum 7/717 two and one-third times greater. The same pattern existed by cycle. When it occurred, breakthrough bleeding lasted an average of approximately 3 days. The total incidence of spotting, defined as bleeding not requiring sanitary protection, was greater with pills containing norethindrone and is shown in Table V.
Cycle 1 Cycle 2 Cycle 3 Cycle 4 Total cycles
Ortho-Novum
717/7
Tri-Norinyl
(%)
(%)
(%)
18.7 17.0 21.5 11.2 17.2
52.6* 40.2* 32.5 30.0t 39.5
65.1* 44.8* 40.2t 43.8* 49.0
Tnphasil
*Versus Triphasil, p <0.001. tVersus Triphasil, p <0.01. Compared with Triphasil, the rate of bleeding with TriNorinyl was nearly three times greater and with OrthoNovum 7/717 more than two times greater. The total incidence of intermenstrual bleeding (spotting and/or breakthrough bleeding) was similar to the previously discussed categories. These patterns hold up for each cycle and are statistically significant when comparing Triphasil to Tri-Norinyl for all cvcles and Triphasil to Ortho-Novum 7/7/7 for three of the four cycles (Table VI). The total incidence of missed pills ranged from 13.1 % to 17.0%. This was similar for all three regimens and lower than the incidence of intermenstrual bleeding (Table VII).
Evaluation of three triphasic oral contraceptives
Vulume 160 "'umber 5, Part 2
1267
Table VII. Correlation between missed pills and intermenstrual bleeding Olllw-Nm'llIll 71717
Tnplzasd MP
(%)
Cvcle 1 Cycle 2 Crcle 3 Cycle 4 Total cycles
13.1 13.0 14.0 12.4 13.1
I
lAW
MP
(%!
(%)
18.7 17.0 21.5 11.2 17.2
11.3 15.2 18.1 11.3 13.9
I
Tn-Nonnyl
1MB
(% )
MP (%)
52.6 40.2 32.5 30.0 39.5
14.7 21.9 15.5 15.7 17.0
1
1MB (%)
65.1 44.8 40.2 43.8 49.0
MP, Missed pills; lAW, intermenstrual bleeding.
The incidence of amenorrhea was slightly higher for Tri-Norinyl (6.3%) than for the other two regimensOrtho-Novum 717 17 (3.4%) and Triphasil (2.3%). One pregnancy occurred during the 1141 cycles. This was caused by a method failure in cycle I involving a patient using Ortho-Novum 717 17. Side effects most frequently reported by patients who continued to take medication were abdominal discomfort, headache, nausea, vomiting, breast discomfort, and dysmenorrhea. The frequency for each of these was relatively similar for each triphasic regimen. No clinically significant changes in blood pressure were noted during the four-cycle follow-up, and no statistically significant changes in weight were observed. The overall rate of continuation for the study was 82%. Discontinuations were for side effects (bleeding and gastrointestinal problems and headaches) and for changes in patients' plans and protocol violations. Comment
Results of this study show little difference among the three preparations in regard to side effects unrelated to cycle control. All were highly effective at preventing pregnancy. Side effects were infrequent and ofthe type commonly associated with oral contraceptive use. The major difference noted among the three contraceptives was the incidence of bleeding irregularities, which was the most common clinical side effect reported with low-dose preparations. The percentage of cycles accompanied by intermenstrual bleeding was significantly lower with the triphasic containing levonorgestrel and ethinyl estradiol (Triphasil) than with the two triphasics containing norethindrone and ethinyl estradiol (Ortho-Novum 717 17 and Tri-Norinyl). Despite numerous theories, the cause of breakthrough bleeding and spotting is not completely understood. lO·'" Bleeding irregularities occur most frequently during the first cycle of oral contraceptive use and tend to decrease and plateau in subsequent cycles.' It is possible" that the difference between progestins and the midcycle increase in estrogen accounts f()r the lower incidence of intermenstrual bleeding observed with the Triphasil regimen. This possibilitv is further
strengthened by the findings for missed pills and intermenstrual bleeding. There was a similar incidence of missed pills for all three regimens; however, the rate of intermenstrual bleeding was lower with the levonorgestrel preparation (Triphasil) than with either of the norethindrone preparations (Ortho-Novum 71717 and Tri-Norinyl). Thus breakthrough bleeding and spotting were not totally a consequence of missed pills but possibly related to the progestin in the pills, resulting in a more stable endometrium. Cycle irregularities (breakthrough bleeding, spotting, and failure of withdrawal bleeding) have been identified as some of the leading causes of patient noncompliance and discontinuation of oral contraceptives. Breakthrough bleeding alone has been characterized as a major deterrent to the use of low-dose oral contraceptives, and amenorrhea is known to be a chief cause of anxiety associated with their use. Reliable statistical data on the various regimen's incidences of these problems can be of great value to the clinician. Selection of a pill known to have an appropriately low frequency of bleeding irregularities can enhance therapy acceptance, reduce patient concerns, and obviate discontinuation in many cases. The significance of the present clinical trial is that it provides the first comparative evaluation ever undertaken of bleeding irregularities associated with the triphasics. Findings indicate that the combination of levonorgestrel and ethinyl estradiol (Triphasil) provides better cycle control with respect to breakthrough bleeding, spotting, and amenorrhea than do the two triphasic oral contraceptives with norethindrone. REFERENCES I. Speroff L. The formulation of oral contraceptives: does
2. 3.
4.
5. 6.
the amount of estrogen make any clinical difference? Johns Hopkins Med J 1982; 150: 170. Goldzieher JW. Hormonal contraception: benefits versus risks. AM J OBSTFT GYNECOL 1987; 157: 1023. Gaspard U.J. Metabolic effects of oral contraceptives. AM J OBSTET GYNECOL 1987;157:1019. Bonnar.J. Coagulation effects of oral contraception. AM .J OBSTET GnJECOI. 1987;157:1042. Hale RW. Phasic approach to oral contraceptives. AM J OBS1'E'1 GY:-.IECOI. 1987; 157: 1052. Hanson MS, Stewart GK, Bechtel RC. et al. Planned par-
1268 Schilling et al.
7.
8. 9. 10.
enthood experience with TriphasiJ. J Reprod Med 1987; 32:592. Cray RH. Patterns of bleeding associated with the use of steroidal contraceptives. In: Diczfalusy E, Fraser IS, Webb FTC, eds. WHO symposium on steroid contraception and endometrial bleeding. Bath, England: Pitman Press Ltd, 1980; 19-21. Toews MR, Boone S. A phase IV Canadian clinical experience trial with Ortho 7/717 tablets. Curr Ther Res 1986;39:336. Woutersz TB, Butler AJ, Cohen M, et aJ. A low-dose triphasic oral contraceptive. Ferti! Steri! 1987;47:425. Maqueo M. Vascular and perivascular changes in the endometrium of women using steroidal contraceptives. In: Diczfalusy E, Fraser IS, Webb FTC, eds. WHO symposium on steroid contraception and endometrial bleeding. Bath, England: Pitman Press Ltd, 1980;139:43.
May 1989 Am J Ob5tet Gynecol
II. Johannisson E, Landgren B-M. Bleeding irregularities with steroidal contraceptives in relation to changes in circulating hormones. In: Diczfalusy E, Fraser IS, Webb FTC, eds. WHO symposium on steroid contraception and endometrial bleeding. Bath, England: Pitman Press Ltd, 1980;291,296,312. 12. Fraser IS, Diczfalusy E. A perspective of steroidal contraception and abnormal bleeding. What are the prospects for improvement? In: Diczfalusy E, Fraser IS, Webb FTC, eds. WHO symposium on steroid contraception and endometrial bleeding. Bath, England: Pitman Press Ltd, 1980:395. 13. Mishell DRJr. Oral steroid contraceptives. In: Mishell DR Jr, Davajan V, eds. Infertility, contraception and reproductive endocrinology. Oradell, New Jersey: Medical Economics, 1986:604.
terindividual variation, the clinician may well improve the efficacy/cycle controll side effects profile experienced by the patients. When it comes to variations in multinational trial data, significant qualitative differences in contraceptive steroid metabolism among geographic areas may yield discrepancies unrelated to experimental design. To reach clinical judgments, the practitioner should probably weigh most heavily the findings derived from populations most similar to his/her own. REFERENCES 1. Back DJ, Bates M, Breckenridge AM, et al. The pharmacokinetics of levonorgestrel and ethynyl estradiol in women-studies with Ovran and Ovranette. Contraception 1981 ;23:229-39. 2. Newburger J, Goldzieher JW. Pharmacokinetics of ethynyl estradiol: a current view. Contraception 1985;32:3344. 3. Nilsson S, Nygren KG. Ethinyl estradiol in peripheral plasma after oral administration of 30 fLg and 50 fLg to women. Contraception 1978; 18:469-75.
May 1989 Am J Obstet Gynecol
4. Back DJ, Bolt HM, Breckenridge AM, et al. The pharmacokinetics of a large (3 mg) oral dose of ethynyl estradiol in women. Contraception 1980;21: 145-53. 5. Back DJ, Breckenridge AM, Crawford FE, et al. An investigation of the pharmacokinetics of ethynyl estradiol in women using radioimmunoassay. Contraception 1979; 20:263-73. 6. Humpel M, Wendt G, Pommerenke G, et al. Investigations of pharmacokinetics of leveonorgestrel to specific consideration of a possible first-pass effect in women. Contraception 1978; 17:207-20. 7. Back DJ, Breckenridge AM, Crawford FE, et al. Kinetics of norethindrone in women II: single-dose kinetics. Clin Pharmacol Ther 1978;24:448-53. 8. Back DJ, Breckenridge AM, Crawford FE, et al. Kinetics of norethindrone in women I: radioimmunoassay and concentrations during multiple dosing. Clin Pharmacol Ther 1978;24. 9. Okerholm RA, Peterson FE, Keeley FJ, et al. Bioavailability of norethindrone in human subjects. Eur J Clin Pharmacol 1978; 13:35-9. 10. Orme ML'E, Back DJ, Breckenridge AM. Clinical pharmacokinetics of oral contraceptive steroids. Clin Pharmacokinet 1983;8:95.
Evaluation of the clinical performance of three triphasic oral contraceptives: A multicenter, randomized comparative trial Lee H. Schilling, MD: O. Thomas Bolding, MD: C. Brandon Chenault, MD; Augusto P. Chong, MD/ Fred Fleury, MD: Katherine Forrest, MD,' Henry I. Glick, MD,g H. M. Hasson, MD: Charles G. Heil, MD,; and Robert S. London, MDj Fresno, California, Birmingham, Alabama, San Antonio, Texas, Hartford, Connecticut, Springfield, Illinois, San Jose, California, Miami, Florida, Chicago, Illinois, Upper Darby, Pennsylvania, and Baltimore, Maryland Three hundred thirteen women partiCipated in an open, multicenter comparison of the incidence of intermenstrual bleeding (breakthrough bleeding and or spotting) assOCiated with the use of three triphasic oral contraceptives. Triphasil (n = 107), containing levonorgestrel and ethinyl estradiol, and Ortho-Novum 71717 (n = 97) and Tri-Norinyl (n = 109), both of which contain norethindrone and ethinyl estradiol, were administered over four cycles for a total of 1141 cycles. The total incidence of intermenstrual bleeding was significantly lower with Triphasil (17.2%) than with Ortho-Novum 71717 (39.5%) or Tri-Norinyl (49.0%). The pattern remained the same when findings were analyzed cycle by cycle and for breakthrough bleeding and spotting separately. The incidence of other side effects was comparable for all regimens. Results of this study demonstrate supenor cycle control with Triphasil compared with Ortho-Novum 71717 and Tri-Norinyl during the first four cycles of use. (AM J OBSTET GVNECOL 1989;160:1264-8.)
Key words: Breakthrough bleeding, intermenstrual bleeding, levonorgestrel, norethindrone, spotting, triphasic oral contraceptives
From Student Health Services," California State University-Fresno, the Brookwood Medical Center.' A Woman's ChOIce,' Mount Sinai Hospital/ the Southern Illznois School of Medlczne: the Planned Parenthood ASSOCIation of Santa Clara County, Inc.,! the Baptist Hospital of Miami,' the ObstetrzcslGynecology Climc, Grant Hos-
1264
pltal.' the Fitzgerald Mercy Hospital,' and the DIVISIOn of ReproductIVe Medlczne,' North Charle5 General Hospital. Reprznt requests: Lee H. Schilling, MD, Student Health SerVices, California State UnIVerSity-Fresno, Fresno, CA 937400081.
Evaluation of three triphasic oral contraceptives
Volume 160 Number 5, Part 2
In the years since the introduction of oral contraceptives, recognition of dose-related cardiovascular and metabolic side effects has led to the development of new dosage forms with reduced steroid content.'-6 At the lowest dose levels necessary to minimize the risks of biochemical alterations, endometrial support may be changed, resulting in an increase in the incidence of intermenstrual bleeding,7 In an attempt to further reduce steroid dose and maintain endometrial integrity, a new approach to oral contraceptive dosing was introduced. Instead of containing fixed ratios of steroid, these new oral contraceptives alter the level of estrogen and/ or progestin in three different phases during the month. Despite hormonal content even lower than that of most low-dose monophasic oral contraceptives, the triphasics have uniformly been claimed to produce a low incidence of bleeding irregularities, even though there is a great variability in the steroidal content and design of each pill." H Y Of the three triphasic formulations available, one uses levonorgestrel as the progestin component, whereas the other two use norethindrone. In one, both hormone levels are varied, whereas in the other two, only the progestin content is altered. To evaluate bleeding patterns associated with individual triphasic formulations, a multicenter, randomized clinical study was undertaken to compare Triphasil (Wyeth-Ayerst Laboratories, Philadelphia, Pa.), containing levonorgestrel and ethinyl estradiol, and Ortho-Novum 717 /7 (Ortho Pharmaceuticals, Raritan, N.J.) and Tri-Norinyl (Syntex Laboratories, Palo Alto, Calif.), both of which contain norethindrone and ethinyl estradiol. The study encompassed the critical first four cycles of use. Material and methods
From 1986 through 1987, healthy, sexually active, female volunteers, between 18 and 37 years of age, were enrolled and treated at JO sites: California (two), Alabama, Florida, Illinois (two), Texas, Maryland, Pennsylvania, and Connecticut. All investigations were approved by the appropriate institutional review boards. After counseling, each volunteer gave informed consent and was screened for contraindications to the use of oral contraceptives. Only subjects who had not used reproductive hormones for at least 1 month and who had no history of irregular menses, amenorrhea, or intermenstrual bleeding within 6 months of enrollment were included. A medical and gynecologic history, including smoking, alcohol use, and dietary habits, was taken, and a physical examination with emphasis on breast and pelvic regions was performed. Weight and blood pressure were recorded at followup visits. Routine laboratory chemistries and Papanicolaou smears were obtained. Normal findings were
1265
Table I. Patient demographics
Total
No.
Age (yr) Mean Range Age (yr) <20 20-24 25-29 ~30
Race White Black Other
Tnphasil
Ortho-Novum 71717
Tn-Nonnyl
107
97
109
23.9 18-35
23.9 18-36
24.3 18-37
14% 52% 20% 14%
19% 42% 26% 13%
16% 44% 26% 15%
74% 12% 14%
76% 9% 14%
69% 17% 15%
required for inclusion in the study. Use of certain medications, such as antibiotics, anticoagulants, aspirin or aspirin-containing medications, isotretinoin, or sedatives, within 14 days of the start of the study or at any time during the study, was prohibited. Screened subjects were randomly assigned to one of the three triphasic oral contraceptives: Triphasil (n = 107), Ortho-Novum 717/7 (n = 97), and TriNorinyl (n = 109) (Table I). Each subject maintained a daily diary card to record pills taken, menstrual and intermenstrual bleeding, symptoms and complaints, and any other medications used. Follow-up visits were scheduled after the first and last treatment cycles. The treatment regimens (Table II) consisted of 21 active tablets, followed by seven inert tablets. Triphasil was started on the first day of bleeding, whereas the other two contraceptives were started on the first Sunday after the onset of bleeding, as directed in each manufacturer's package insert. Thereafter, tablets from each package of pills were taken serially for 28 days. The incidence of intermenstrual bleeding, breakthrough bleeding, spotting, and amenorrhea during treatment was compared among groups by means of Fisher's exact test. Results
A total of 313 subjects participated in at least one cycle of treatment for an overall total of 1141 cycles for all regimens. The number of subjects per cycle is shown in Table III. During treatment, cycle length was similar for each regimen (27.2 to 28.1 days). Length of menses was also similar (4.4 to 4.7 days). Latent period before onset of withdrawal bleeding ranged from l.1 to 2.3 days. To eliminate possible bias arising from the difference in starting day (day I for Triphasil and the first Sunday after onset of menses for Ortho-Novum 7/717 and TriNorinyl), bleeding data were analyzed both with and without the first 7 days of pill consumption during cycle
1266 Schilling et al.
Am
May 1989
J Obstet Gynecol
Table II. Hormonal content of three triphasic regimens Progestm
Regimen
Triphasil Phase 1 Phase 2 Phase 3 Ortho-Novum 7/7/7 Phase 1 Phase 2 Phase 3 Tri-Norinyl Phase 1 Phase 2 Phase 3
Levonorgestrel Levonorgestrel Levonorgestrel
50 75 125
Ethinyl estradiol Ethinyl estradiol Ethinyl estradiol
30 40 30
6 5 10
Norethindrone Norethindrone Norethindrone
500 750 1,000
Ethinyl estradiol Ethinyl estradiol Ethinyl estradiol
35 35 35
7 7 7
Norethindrone Norethindrone Norethindrone
500 1,000 500
Ethinyl estradiol Ethinyl estradiol Ethinyl estradiol
35 35 35
7 9 5
Table III. Study population
Table V. Total incidence of spotting by individual and total cycles
Ortho-Novum
71717
Tnphasil (%)
Total cycles Total woman-years Total subjects Cycle 1 Cycle 2 Cycle 3 Cycle 4
Tn-Nonnyl (%)
(%)
389 29.9
352 27.1
107 107 100 93 89
No. of days
Estrogen
J.Lg
400 30.8 109 109 105 97 89
97 97 92 83 80
Tnphaszl (%)
Cycle 1 Cycle 2 Cycle 3 Cycle 4 Total cycles
OrtilO-Novum
71717
17.8 14.0 17.2 10.1 14.9
(%)
Tn-Norinyl (%)
48.5* 34.8* 28.9 25.0t 34.9
56.9* 34.3t 30.9* 39.3* 40.8
*Versus Triphasil, p < 0.001. tVersus Triphasil, p < 0.0 I. tVersus Triphasil. p < 0.05.
Table IV. Total incidence of breakthrough bleeding by individual and total cycles Ortho-Novum
Cycle 1 Cycle 2 Cycle 3 Cycle 4 Total cycles
Table VI. Total incidence of intermenstrual bleeding by individual and total cycles
TriPhasil (%)
71717 (%)
Tn-Norinyl (%)
6.5 10.0 11.8 6.7 8.7
29.9* 26.1t 20.5 17.5* 23.9
39.4* 28.6* 24.7* 20.2* 28.8
*Versus Triphasil, p < 0.001. tVersus Triphasil, p < 0.01. *Versus Triphasil, p < 0.05.
1. No difference was found to result from the dissimilar starting days. The total incidence of breakthrough bleeding, defined as bleeding requiring sanitary protection, was different for each of the triphasic regimens (Table IV). Compared with Triphasil, the rate of bleeding with TriNorinyl was almost three times greater and with OrthoNovum 7/717 two and one-third times greater. The same pattern existed by cycle. When it occurred, breakthrough bleeding lasted an average of approximately 3 days. The total incidence of spotting, defined as bleeding not requiring sanitary protection, was greater with pills containing norethindrone and is shown in Table V.
Cycle 1 Cycle 2 Cycle 3 Cycle 4 Total cycles
Ortho-Novum
717/7
Tri-Norinyl
(%)
(%)
(%)
18.7 17.0 21.5 11.2 17.2
52.6* 40.2* 32.5 30.0t 39.5
65.1* 44.8* 40.2t 43.8* 49.0
Tnphasil
*Versus Triphasil, p <0.001. tVersus Triphasil, p <0.01. Compared with Triphasil, the rate of bleeding with TriNorinyl was nearly three times greater and with OrthoNovum 7/717 more than two times greater. The total incidence of intermenstrual bleeding (spotting and/or breakthrough bleeding) was similar to the previously discussed categories. These patterns hold up for each cycle and are statistically significant when comparing Triphasil to Tri-Norinyl for all cvcles and Triphasil to Ortho-Novum 7/7/7 for three of the four cycles (Table VI). The total incidence of missed pills ranged from 13.1 % to 17.0%. This was similar for all three regimens and lower than the incidence of intermenstrual bleeding (Table VII).
Evaluation of three triphasic oral contraceptives
Vulume 160 "'umber 5, Part 2
1267
Table VII. Correlation between missed pills and intermenstrual bleeding Olllw-Nm'llIll 71717
Tnplzasd MP
(%)
Cvcle 1 Cycle 2 Crcle 3 Cycle 4 Total cycles
13.1 13.0 14.0 12.4 13.1
I
lAW
MP
(%!
(%)
18.7 17.0 21.5 11.2 17.2
11.3 15.2 18.1 11.3 13.9
I
Tn-Nonnyl
1MB
(% )
MP (%)
52.6 40.2 32.5 30.0 39.5
14.7 21.9 15.5 15.7 17.0
1
1MB (%)
65.1 44.8 40.2 43.8 49.0
MP, Missed pills; lAW, intermenstrual bleeding.
The incidence of amenorrhea was slightly higher for Tri-Norinyl (6.3%) than for the other two regimensOrtho-Novum 717 17 (3.4%) and Triphasil (2.3%). One pregnancy occurred during the 1141 cycles. This was caused by a method failure in cycle I involving a patient using Ortho-Novum 717 17. Side effects most frequently reported by patients who continued to take medication were abdominal discomfort, headache, nausea, vomiting, breast discomfort, and dysmenorrhea. The frequency for each of these was relatively similar for each triphasic regimen. No clinically significant changes in blood pressure were noted during the four-cycle follow-up, and no statistically significant changes in weight were observed. The overall rate of continuation for the study was 82%. Discontinuations were for side effects (bleeding and gastrointestinal problems and headaches) and for changes in patients' plans and protocol violations. Comment
Results of this study show little difference among the three preparations in regard to side effects unrelated to cycle control. All were highly effective at preventing pregnancy. Side effects were infrequent and ofthe type commonly associated with oral contraceptive use. The major difference noted among the three contraceptives was the incidence of bleeding irregularities, which was the most common clinical side effect reported with low-dose preparations. The percentage of cycles accompanied by intermenstrual bleeding was significantly lower with the triphasic containing levonorgestrel and ethinyl estradiol (Triphasil) than with the two triphasics containing norethindrone and ethinyl estradiol (Ortho-Novum 717 17 and Tri-Norinyl). Despite numerous theories, the cause of breakthrough bleeding and spotting is not completely understood. lO·'" Bleeding irregularities occur most frequently during the first cycle of oral contraceptive use and tend to decrease and plateau in subsequent cycles.' It is possible" that the difference between progestins and the midcycle increase in estrogen accounts f()r the lower incidence of intermenstrual bleeding observed with the Triphasil regimen. This possibilitv is further
strengthened by the findings for missed pills and intermenstrual bleeding. There was a similar incidence of missed pills for all three regimens; however, the rate of intermenstrual bleeding was lower with the levonorgestrel preparation (Triphasil) than with either of the norethindrone preparations (Ortho-Novum 71717 and Tri-Norinyl). Thus breakthrough bleeding and spotting were not totally a consequence of missed pills but possibly related to the progestin in the pills, resulting in a more stable endometrium. Cycle irregularities (breakthrough bleeding, spotting, and failure of withdrawal bleeding) have been identified as some of the leading causes of patient noncompliance and discontinuation of oral contraceptives. Breakthrough bleeding alone has been characterized as a major deterrent to the use of low-dose oral contraceptives, and amenorrhea is known to be a chief cause of anxiety associated with their use. Reliable statistical data on the various regimen's incidences of these problems can be of great value to the clinician. Selection of a pill known to have an appropriately low frequency of bleeding irregularities can enhance therapy acceptance, reduce patient concerns, and obviate discontinuation in many cases. The significance of the present clinical trial is that it provides the first comparative evaluation ever undertaken of bleeding irregularities associated with the triphasics. Findings indicate that the combination of levonorgestrel and ethinyl estradiol (Triphasil) provides better cycle control with respect to breakthrough bleeding, spotting, and amenorrhea than do the two triphasic oral contraceptives with norethindrone. REFERENCES I. Speroff L. The formulation of oral contraceptives: does
2. 3.
4.
5. 6.
the amount of estrogen make any clinical difference? Johns Hopkins Med J 1982; 150: 170. Goldzieher JW. Hormonal contraception: benefits versus risks. AM J OBSTFT GYNECOL 1987; 157: 1023. Gaspard U.J. Metabolic effects of oral contraceptives. AM J OBSTET GYNECOL 1987;157:1019. Bonnar.J. Coagulation effects of oral contraception. AM .J OBSTET GnJECOI. 1987;157:1042. Hale RW. Phasic approach to oral contraceptives. AM J OBS1'E'1 GY:-.IECOI. 1987; 157: 1052. Hanson MS, Stewart GK, Bechtel RC. et al. Planned par-
1268 Schilling et al.
7.
8. 9. 10.
enthood experience with TriphasiJ. J Reprod Med 1987; 32:592. Cray RH. Patterns of bleeding associated with the use of steroidal contraceptives. In: Diczfalusy E, Fraser IS, Webb FTC, eds. WHO symposium on steroid contraception and endometrial bleeding. Bath, England: Pitman Press Ltd, 1980; 19-21. Toews MR, Boone S. A phase IV Canadian clinical experience trial with Ortho 7/717 tablets. Curr Ther Res 1986;39:336. Woutersz TB, Butler AJ, Cohen M, et aJ. A low-dose triphasic oral contraceptive. Ferti! Steri! 1987;47:425. Maqueo M. Vascular and perivascular changes in the endometrium of women using steroidal contraceptives. In: Diczfalusy E, Fraser IS, Webb FTC, eds. WHO symposium on steroid contraception and endometrial bleeding. Bath, England: Pitman Press Ltd, 1980;139:43.
May 1989 Am J Ob5tet Gynecol
II. Johannisson E, Landgren B-M. Bleeding irregularities with steroidal contraceptives in relation to changes in circulating hormones. In: Diczfalusy E, Fraser IS, Webb FTC, eds. WHO symposium on steroid contraception and endometrial bleeding. Bath, England: Pitman Press Ltd, 1980;291,296,312. 12. Fraser IS, Diczfalusy E. A perspective of steroidal contraception and abnormal bleeding. What are the prospects for improvement? In: Diczfalusy E, Fraser IS, Webb FTC, eds. WHO symposium on steroid contraception and endometrial bleeding. Bath, England: Pitman Press Ltd, 1980:395. 13. Mishell DRJr. Oral steroid contraceptives. In: Mishell DR Jr, Davajan V, eds. Infertility, contraception and reproductive endocrinology. Oradell, New Jersey: Medical Economics, 1986:604.