Estrogen-progestin combinations are contraceptive combinations containing estrogenic and progestinic steroids.
Oral, intravaginal, and transdermal estrogen-progestin combinations are used for prevention of conception in women who elect to use one of these preparations as a method of contraception. When taken according to the prescribed regimen, these contraceptives provide almost completely effective contraception.
The pregnancy rate in women using conventional-dosage oral contraceptives (containing 35 mcg or more of ethinyl estradiol or 50 mcg or more of mestranol) is generally reported as less than one pregnancy per 100 woman-years of use. Slightly higher rates (somewhat more than one pregnancy per 100 woman-years) reportedly occur with some oral preparations containing 35 mcg or less of ethinyl estradiol, and rates of about 3 pregnancies per 100 woman-years reportedly occur with oral contraceptives containing progestins only. The pregnancy rate in women using the vaginal contraceptive ring containing ethinyl estradiol and etonogestrel (NuvaRing®) is reported as 1-2 pregnancies per 100 women-years of use.309 The pregnancy rate in women using the transdermal contraceptive system containing ethinyl estradiol and norelgestromin (Ortho Evra®) is reported as approximately one pregnancy per 100 women-years of use.308 Five out of the 15 pregnancies reported in large clinical trials in women using the transdermal contraceptive system Ortho Evra® occurred in women with a baseline weight of 90 kg or more; these data suggest that Ortho Evra® may be less effective in such women than in those with a lower body weight.308 Pregnancy rates for other methods of contraception reportedly range from about less than 1-6 pregnancies per 100 woman-years for intrauterine devices (IUDs) to about 14-47 pregnancies per 100 woman-years for the calendar method of periodic abstinence (rhythm). The pregnancy rate when no method of contraception is used is about 60-80 pregnancies per 100 woman-years. Pregnancy rates are derived from various studies conducted by different investigators in different population groups and, therefore, cannot be compared precisely.
Because a positive association between the dose of estrogens in oral contraceptives and the risk of thromboembolism has been shown in at least 2 studies, it is prudent and therapeutically desirable to minimize exposure to estrogens; therefore, the oral contraceptive used in a given patient should be that preparation which contains the least amount of estrogen and is compatible with an acceptable pregnancy rate and patient acceptance. Following a recommendation by the US Food and Drug Administration's (FDA) Fertility and Maternal Health Drugs Advisory Committee, oral contraceptive preparations containing more than 50 mcg of estrogen were discontinued in 1988 since these formulations were considered no more effective than those containing lower dosages of estrogen.222
Because the pharmacokinetic profile for the transdermal contraceptive system containing ethinyl estradiol and norelgestromin (Ortho Evra®) differs from the profile for oral contraceptive preparations308 , the clinician and patient must weigh the possible risks of higher estrogen exposure with Ortho Evra® against the possibility of pregnancy if the oral contraceptive is not taken according to the prescribed regimen.308 Increased exposure to estrogen may increase the risk of certain adverse effects (e.g., venous thromboembolism).308
The clinician and patient must weigh the possible risks of estrogen-progestin contraception against those of other methods of contraception or no contraception. In addition, potential noncontraceptive benefits associated with use of oral contraceptives can be considered.
A short-course, high-dose regimen of an oral estrogen-progestin combination is used in women for the prevention of conception after unprotected intercourse (postcoital contraception, morning-after pills) as an emergency contraceptive (EC)†.254, 255, 257, 258, 259, 261, 262, 264, 265, 345, 346, 347, 348, 349 If taken soon enough after intercourse (i.e., within 72-120 hours),345, 346, 347 the combination regimen can prevent not terminate pregnancy; therefore, the regimen is contraceptive not abortifacient.265, 284, 286
Several regimens employing high-dose combinations of ethinyl estradiol and norgestrel or levonorgestrel have been used safely and effectively for postcoital contraception†.254, 255, 257, 258, 259, 261, 262, 264, 265, 268 One widely studied and used regimen (the Yuzpe regimen) consists of administering 2 tablets containing 50 mcg of ethinyl estradiol and 0.5 mg of norgestrel each (i.e., a dose of 100 mcg and 1 mg, respectively) within 72 hours after unprotected intercourse, repeating this dose 12 hours later.254, 255, 257, 258, 259, 261, 262, 264, 265, 345 Alternative combination regimens consisting of 100-120 mcg of ethinyl estradiol and 1.2 mg of norgestrel or 0.5-0.6 mg of levonorgestrel administered within 72 hours of intercourse and repeated 12 hours later also have been used.264, 265, 282, 345 Raw pregnancy (failure) rates in trials employing such regimens have ranged from 0.2-7.4%.254, 255, 256, 257, 258, 259, 260, 261, 265, 285, 287 However, not all women given emergency postcoital contraception are at genuine risk for pregnancy, since unprotected intercourse that occurs in the early follicular or in the luteal phase is unlikely to result in conception.259 Therefore, a more accurate indication of efficacy would be based on the timing of unprotected intercourse and the probability that pregnancy would occur without treatment.256, 259 When efficacy of postcoital contraception with such estrogen-progestin combination regimens is based on the likelihood of pregnancy (computed by matching the cycle day of unprotected intercourse with known conception rates for that cycle day), estimates from various studies of the proportionate reduction in pregnancy risk have ranged from about 55-94%, and pooled analysis of data from studies employing the Yuzpe regimen reveal that such therapy is approximately 74% (confidence interval: 68.2-79.3%) effective in preventing a single pregnancy.256, 257, 265, 284, 286, 287 Because of study limitations of this pooled analysis, it is likely that true efficacy rates are higher than this estimate, perhaps exceeding 80%.257 However, postcoital (emergency) contraceptive regimens are not as effective as most other forms of long-term contraception.345, 346 The efficacy of postcoital regimens employing lower estrogen/progestin doses currently is not known.262, 278
An emergency contraceptive regimen employing a progestin alone (levonorgestrel) appears to be more effective and better tolerated than the estrogen-progestin emergency contraceptive (“Yuzpe”) regimen when the regimens are initiated within 72 hours of unprotected intercourse, and therefore, the progestin-alone regimen generally is preferred when readily available.345, 346, 347, 348
To prevent pregnancy, oral estrogen-progestin combination therapy ideally should begin within 72 hours following coitus.254, 261, 262, 265, 278, 285, 286 Studies show that emergency contraception is moderately effective when the first dose is administered up to 120 hours after unprotected intercourse.345, 346, 347 Postcoital contraceptive efficacy diminishes as the time period between intercourse and administration of the combination increases,254, 264, 277, 287, 345, 346, 347, 348 with the regimen becoming completely ineffective by day 6 or 7, when implantation usually occurs.254, 264, 277, 287
Because of the short time frame for effective postcoital use, women should be informed of the availability of postcoital contraception before such use is warranted and offered advanced provision (e.g., provided a prescription for emergency contraception at the time of a routine gynecology visit), advised of the availability of an over-the-counter (OTC) emergency contraceptive preparation, or advised to contact a clinician immediately if the need arises.253, 262, 329, 345 By informing women of this emergency option and advising them of steps to take to readily obtain the combinations before or when needed, effective postcoital contraception ultimately could reduce substantially the number of unintended pregnancies and induced abortions.262, 278, 281 Because of the high incidence of adverse effects (e.g., nausea and vomiting with estrogen-progestin combinations) decreased contraceptive efficacy compared with conventional long-term contraceptive methods, including cyclic use of estrogen-progestin combinations, postcoital contraception with the combinations generally should be limited to emergency situations following unprotected intercourse (e.g., rape, contraceptive failure, missed doses of oral or parenteral contraceptives, lack of planning).265, 268, 278, 284, 345, 346 Postcoital contraceptive regimens should not be used as a routine method of contraception.345, 346 Women should be informed that postcoital contraceptives do not protect against human immunodeficiency virus (HIV) infection or other sexually transmitted diseases.285, 290, 365, 366, 367, 368 Women should be advised about various available routine methods of contraception when given emergency contraception and instructed as to when to begin an effective method of such contraception; the potential value of condoms as a supplement to other methods (e.g., to reduce the risk of sexually transmitted diseases) also should be discussed.253, 255, 261, 263, 265, 278, 284 Women who request emergency contraceptives repeatedly should be informed about other contraceptive options.345, 350
The American College of Obstetricians and Gynecologists (ACOG),326 other experts,324, 325, 326 and some states (e.g., Alaska, California, Hawaii, Maine, New Mexico, Washington)325 have advocated increased access to emergency postcoital contraception (e.g., nonprescription access via pharmacies, advance provision by clinicians) as a means of decreasing unintended pregnancy and abortion rates. There is some evidence that increased access to emergency postcoital contraception may not compromise conventional contraceptive use or sexual behavior,324, 325, 326 potentially allaying some concerns that have prompted others to advocate for restricted access. The US Food and Drug Administration (FDA) has approved one postcoital contraceptive (Plan B® One-Step; levonorgestrel) for nonprescription (OTC) status for women 17 years of age or older; the contraceptive will remain a prescription-only preparation for women younger than 17 years of age.329
Use of high-dose oral estrogen-progestin combinations as emergency postcoital contraception may cause menstrual cycle disruption; if menstruation is delayed by a week or more, a sensitive pregnancy test should be performed.258, 259, 260, 262, 264, 265, 345 If pregnancy has already occurred, there is little, if any, evidence that postcoital regimens will adversely affect the fetus or pregnancy.254, 260, 263, 265, 270, 271, 272, 273, 274, 282, 285, 286 Because postcoital regimens may not prevent ectopic (tubal or abdominal) pregnancies, women receiving such regimens should be informed that ectopic pregnancy is a medical emergency and to consult their clinician immediately if spotting or cramping occurs (usually beginning shortly after the first missed period with such pregnancy).265, 291 Women should consult their clinician regarding when they can start or resume cyclic oral contraceptive regimens with a combination; they also should be instructed carefully regarding differences in administration schedule and any differences in formulation (e.g., potency, active versus inert tablets) of the preparations.265
Contraception and Folate Supplementation
Certain estrogen-progestin combinations (Beyaz® [ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg and levomefolate calcium 0.451 mg], Safyral®[ethinyl estradiol 30 mcg in fixed combination with drospirenone 3 mg and levomefolate calcium 0.451 mg]) are used in women choosing oral contraceptives as their method of contraception, for the additional purpose of increasing folate concentrations to reduce the risk of fetal neural tube defects when conception occurs while the woman is receiving the contraceptive or shortly after the contraceptive is discontinued.367, 368 The US Preventive Services Task Force recommends that women of childbearing age receive supplemental folic acid at a dosage of at least 0.4 mg daily.367, 368 Other folate supplementation that a woman may be taking should be considered before prescribing ethinyl estradiol in combination with drospirenone and levomefolate calcium (Beyaz®, Safyral®).367, 368 Folate supplementation should be maintained if a woman discontinues this contraceptive because of pregnancy.367, 368
Certain triphasic or estrophasic oral estrogen-progestin combinations (specifically, Ortho Tri-Cyclen® [ethinyl estradiol 35 mcg in fixed combination with norgestimate 0.18, 0.215, or 0.25 mg], or Estrostep® [ethinyl estradiol 20, 30, or 35 mcg in fixed combination with norethindrone acetate 1 mg]) can be used for the treatment of moderate acne vulgaris in females 15 years of age or older who have no known contraindications to oral contraceptive therapy, desire contraception, have achieved menarche, and are unresponsive to topical anti-acne medication. The manufacturer of Estrostep® states that the drug should be used for the treatment of acne vulgaris only in women who desire oral contraception and plan to take the drug for at least 6 months.299 Acne is a skin condition with a multifactorial etiology and the combination of ethinyl estradiol and norgestimate may increase sex hormone-binding globulin (SHBG) and decrease free testosterone serum concentrations. This may result in a decrease in the severity of facial acne in otherwise healthy women. In two double-blind, placebo-controlled, 6-month multicenter trials, therapy with the ethinyl estradiol/norgestimate combination resulted in clinically important decreases in inflammatory lesion count and total lesion count as compared with placebo (56.6% versus 36.6% and 49.6% versus 30.3%, respectively). In two 6-month, randomized, double-blind, placebo-controlled, multicenter studies in young women (mean age: 24 years) with acne vulgaris, therapy with the ethinyl estradiol/norethindrone combination or placebo resulted in a 52 or 41% reduction in inflammatory lesion count, respectively, and a 43 or 32% reduction in total lesion count, respectively.299, 306
The estrogen-progestin combinations (specifically, Yaz® [ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg], Beyaz® [ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg and levomefolate calcium 0.451 mg]) also are used for the treatment of moderate acne vulgaris in females at least 14 years of age who have no known contraindications to oral contraceptive therapy and who desire oral contraception and have achieved menarche.366, 367
Premenstrual Dysphoric Disorder
The estrogen-progestin combinations (Yaz® [ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg], Beyaz® [ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg and levomefolate calcium 0.451 mg]) are used for the treatment of premenstrual dysphoric disorder (formerly known as late luteal phase dysphoric disorder) in women who desire oral contraception.366, 367 Efficacy of ethinyl estradiol in combination with drospirenone (Yaz®) has been evaluated in 2 randomized, placebo-controlled, double-blind studies of 3 months' duration in adult women who met DSM-IV criteria for premenstrual dysphoric disorder.338, 341, 366, 367 In these studies, ethinyl estradiol in combination with drospirenone was found to be superior to placebo in improving symptoms associated with this disorder.338, 341, 366, 367 Efficacy of ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg (Yaz®) or ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg and levomefolate calcium 0.451 mg (Beyaz®) when used for more than 3 menstrual cycles has not been evaluated.366, 367
Estrogen-progestin preparations have been used for the treatment of endometriosis† or dysfunctional uterine bleeding†.
Estrogen-progestin combination contraceptives are administered orally, intravaginally, and percutaneously by topical application of a transdermal system to the skin.
To ensure maximum contraceptive efficacy, oral contraceptives should be taken as near as possible to the same time each day (i.e., at regular 24-hour intervals). Most oral contraceptives are commercially available in a mnemonic dispensing package that is designed to aid the user in complying with the prescribed dosage schedule; these containers should be used whenever possible.
To minimize nausea, oral contraceptives should be taken with or after the evening meal or at bedtime. As vomiting or diarrhea may decrease absorption of oral contraceptives and potentially result in treatment failures, a back-up method of contraception (e.g., condoms, foam, sponge) should be used until the next clinician contact.295, 296, 298, 299, 301
Chewable tablets may be swallowed whole or chewed and consumed with 240 mL of liquid.337
Patients receiving the vaginal contraceptive ring containing ethinyl estradiol and etonogestrel (NuvaRing®) should be carefully instructed in the use of the vaginal ring.309 To obtain optimum results, patients also should be given a copy of the patient information provided by the manufacturer.309 The ring should be inserted into the vagina by the patient; the manufacturer states that the exact position of the ring inside the vagina is not critical for its proper functioning.309 If the ring is accidentally expelled, it can be rinsed with cool or lukewarm water and reinserted or, if necessary, a new ring should be inserted as soon as possible; in either case, the administration schedule employed should be continued.309 If the contraceptive ring has been out of the vagina for longer than 3 hours, a back-up method of contraception (e.g., condoms, spermicides) must be used until the ring has been used continuously for 7 days.309
Women receiving the transdermal contraceptive containing ethinyl estradiol and norelgestromin (Ortho Evra®) should be instructed in the use of the transdermal system.308 To obtain optimum results, women also should be given a copy of the patient information provided by the manufacturer.308 The transdermal system is applied topically to a clean and dry area of intact skin on the buttock, abdomen, upper outer arm, or upper torso, by firmly pressing the system with the adhesive side touching the skin.308 The system should be pressed firmly in place with the palm of the hand for about 10 seconds, ensuring good contact, particularly around the edges.308 The application site should not be oily, damaged, or irritated.308 The transdermal system should not be applied to the breasts or to areas where tight clothing may cause the system to be rubbed off.308, 308 If the system inadvertently gets detached during the period of use, and is off for less than one day, the system may be reapplied or, if necessary, a new system (if the system is no longer sticky) may be applied; in either case, the application schedule employed should be continued.308 If the system is off for longer than one day or for an unknown duration, a new system should be applied immediately and a new 4-week cycle should be started; a back-up method of contraception (e.g., condoms, spermicides, diaphragm) must be used for the first week of the new cycle.308 Patients should be instructed to handle the used transdermal system carefully (e.g., fold the system in half with the sticky sides together) and then discard the system.308
Postcoital contraceptive regimens usually consist of 2-5 tablets per dose† administered 12 hours apart.254, 255, 257, 258, 260, 261, 262, 264, 265, 345 The first dose should be administered as soon as possible but preferably within 72 hours following unprotected intercourse; the second dose is administered 12 hours later.254, 255, 257, 258, 260, 261, 262, 264, 265, 345, 346, 347 Women should be advised of the importance of taking the second dose 12 hours after the initial dose, and to schedule the first dose as conveniently as possible so that the likelihood of missing the second dose 12 hours later is minimized (e.g., if the first dose were taken at 3 p.m., the second dose would need to be taken at 3 a.m., which might present a problem of compliance for heavy sleepers).265, 275, 282, 284, 285 The first dose can be taken up to 120 hours after unprotected intercourse if necessary, but efficacy decreases as initiation of contraception becomes more remote from unprotected intercourse.345, 346, 347
Because the high dosage in the combination regimens may cause severe nausea and vomiting in a substantial proportion of women,254, 255, 257, 258, 260, 261, 262, 264, 265, 285 which could limit compliance with postcoital contraception, use of an antiemetic 1 hour prior to administration of the first dose of the combination should be considered.254, 255, 257, 258, 259, 260, 261, 262, 264, 265, 282, 284, 286, 345 Administering the dose with food is not effective in reducing adverse GI effects (i.e., nausea).345, 346 If vomiting does occur within 2 hours after administration of a dose of the estrogen-progestin combination, consideration should be given to repeating the dose.345
Because of the short time frame of effective postcoital use (i.e., therapy must commence within 72-120 hours of unprotected intercourse), clinicians ideally should inform women of the availability of postcoital contraception before such use is warranted, advising them to contact a clinician immediately if the need for such contraception arises.253, 262, 345, 346, 347 Alternatively, women can be given an appropriate estrogen-progestin combination in advance, with careful instructions on how to safely and effectively use the combination for emergency postcoital contraception; if a supply of the drugs is given to a woman in advance, she also should be advised that postcoital contraceptives are for emergency situations (e.g., unprotected intercourse, missed doses of oral contraceptives, missed parenteral contraceptive dose, contraceptive failure) only and should not be employed as the primary method of contraception.262, 265, 278, 282, 284
If the menstrual period is delayed by a week or more, or if persistent irregular bleeding or lower abdominal pain occurs, professional medical follow-up care should be obtained.265, 282, 284, 345
Before initiating therapy, women receiving estrogen-progestin contraceptives should be given a copy of the patient labeling for the drugs.
Estrogen-progestin oral contraceptives are usually classified according to their formulation:
Although the progestin content of the formulations also varies, oral contraceptives usually are described in terms of their estrogen content. The estrogenic and progestinic dominance of oral contraceptives depends mainly on the amount of estrogen and the amount and specific progestin contained in the formulation. The estrogenic or progestinic dominance of an oral contraceptive may contribute to hormone-related adverse effects and may be useful in selecting an alternate formulation when unacceptable adverse effects occur with a given formulation.
Whenever possible, the smallest dosage of estrogen and progestin should be used. The amount of both hormones should be considered in the choice of an oral contraceptive preparation. It is prudent and in keeping with good principles of therapeutics to minimize exposure to estrogen and progestin. The combination used should be one which contains the least amount of estrogen and progestin that is compatible with a low failure rate and with the individual needs of the woman. Common adverse effects are usually most pronounced during the first oral contraceptive cycle and generally disappear or diminish after 3 or 4 cycles; there does not appear to be any advantage in changing preparations during this period. If minor adverse effects persist after the fourth cycle, a different combination of drugs or a different dosage may be tried.
Most fixed combinations are available as 21- or 28-day dosage preparations (conventional-cycle oral contraceptives). Some 28-day preparations contain 21 hormonally active tablets and 7 inert or ferrous fumarate-containing tablets; other 28-day preparations contain 24 hormonally active tablets and 4 inert or ferrous fumarate-containing tablets. In establishing an oral contraceptive dosage cycle, the menstrual cycle is usually considered to be 28 days. The first day of bleeding is counted as the first day of the cycle.
One fixed-combination extended-cycle oral contraceptive (e.g., Seasonale®) is available as a 91-day dosage preparation containing 84 hormonally active tablets and 7 inert tablets.322 Other extended-cycle oral contraceptive preparations (e.g., LoSeasonique®, Seasonique®,) are available as 91-day preparations with 84 hormonally active tablets containing estrogen/progestin and 7 tablets containing low-dose estrogen.331, 354
One fixed-combination continuous-regimen (noncyclic) oral contraceptive (i.e., Lybrel®) is available as a 28-day dosage preparation containing 28 hormonally active tablets.339
Conventional-cycle Oral Contraceptives
Administration of monophasic fixed-combination conventional-cycle oral contraceptives usually begins on the first day of the menstrual cycle or on the first Sunday after menstrual bleeding has started. A back-up method of contraception (e.g., condoms, foam, sponge) should be employed for 7 days following initiation of oral contraceptive therapy if the first dose of the oral contraceptive is begun on the first Sunday after menstrual bleeding starts.295, 296, 298, 299, 301, 332, 366 A back-up method of contraception is not needed if the first dosage cycle is initiated on the first day of the menstrual cycle.295, 296, 298, 299, 301 When the 21-day conventional-cycle preparations are used, tablets containing estrogen/progestin are administered once daily for 21 consecutive days, followed by up to 7 days without drugs. When the 28-day dosage preparations containing 21 hormonally active tablets are used, tablets containing estrogen/progestin are administered once daily for 21 consecutive days, followed by inert tablets or tablets containing ferrous fumarate for 7 days. When the 28-day dosage preparations containing 24 hormonally active tablets are used, tablets containing estrogen/progestin are administered once daily for 24 consecutive days, followed by inert tablets or tablets containing ferrous fumarate for 4 days. Withdrawal bleeding usually occurs within 2 or 3 days after the last hormonally active tablet has been taken. Repeat dosage cycles begin on the same day of the week as the initial cycle. Repeat cycles should generally begin regardless of whether menstruation has stopped; after several cycles of fixed-combination preparations, menstrual flow may be considerably reduced. If a repeat 21-day cycle is started later than the eighth day after taking the last hormonally active tablet (or later than the next day after taking the last inactive tablet with 28-day dosage preparations), a back-up method of contraception should be employed until the patient has taken a hormonally active tablet daily for 7 consecutive days.295
When a biphasic oral contraceptive (e.g., Ortho-Novum® 10/11) is used, each dosage cycle consists of 2 sequentially administered fixed combinations; the first sequence consists of 10 tablets containing a fixed combination of low-dose estrogen and low-dose progestin and the second sequence consists of 11 tablets containing a fixed combination of low-dose estrogen and higher-dose progestin. Although biphasic oral contraceptives consist of 2 sequentially administered fixed combinations, they are not the same as previously available “sequential” oral contraceptives which consisted of an estrogen alone for the first sequence. Administration of a biphasic oral contraceptive usually begins on the first Sunday after or on which bleeding has started. Tablets from the first sequence are administered once daily for 10 consecutive days, followed by once-daily administration of tablets from the second sequence for 11 consecutive days and then a period of 7 days without drug; when a 28-day dosage preparation is used, inert tablets are administered during this latter 7-day period. A back-up method of contraception (e.g., condoms, foam, sponge) should be employed for 7 days following initiation of oral contraceptive therapy if the first dose of the oral contraceptive is begun on the first Sunday on or after menstrual bleeding starts; a back-up method of contraception is not necessary if the first dosage cycle is initiated on the first day of the menstrual cycle.298 Repeat dosage cycles begin on the eighth day after taking the last hormonally active tablet.
Triphasic oral contraceptives contain graduated sequences of progestin or estrogen.294, 299 With most commercially available triphasic oral contraceptives (e.g., Ortho-Novum® 7/7/7, Ortho-Tri-Cyclen®, Ortho-Tri-Cyclen® Lo, Tri-Levlen®, Tri-Norinyl®, Triphasil®), each dosage cycle consists of 3 sequentially administered fixed combinations of the hormones in which the ratio of progestin to estrogen progressively increases with each sequence. The first sequence consists of tablets containing a fixed combination of low-dose estrogen and low-dose progestin, the second sequence consists of tablets containing a fixed combination of low-dose (i.e., Ortho-Novum 7/7/7, Ortho-Tri-Cyclen®, Ortho-Tri-Cyclen® Lo, Tri-Norinyl®) or low but slightly higher-dose estrogen (i.e., Tri-Levlen®, Triphasil®) and higher-dose progestin, and the third sequence consists of tablets containing low-dose estrogen and either an even higher-dose progestin (i.e., Ortho-Novum® 7/7/7, Ortho-Tri-Cyclen®, Ortho-Tri-Cyclen® Lo, Tri-Levlen®, Triphasil®) or low-dose progestin (i.e., Tri-Norinyl®).
Triphasic oral contraceptives in which the estrogen component progressively increases with each sequence also are available; such contraceptives have been referred to as “estrophasic”.294, 299 With the currently commercially available estrophasic oral contraceptive (e.g., Estrostep®), the first sequence consists of tablets containing a fixed combination of a progestin and low-dose estrogen, the second sequence consists of tablets containing a fixed combination of a progestin and a slightly higher dosage of an estrogen, and the third sequence consists of tablets containing a progestin and an even higher dosage of an estrogen.299
Administration of a triphasic oral contraceptive usually begins on the first Sunday after or on which bleeding has started or on the first day of the menstrual cycle. Tablets from the first sequence of Ortho-Novum® 7/7/7, Ortho-Tri-Cyclen®, or Ortho-Tri-Cyclen® Lo are administered once daily for 7 consecutive days, followed by once-daily administration of tablets from the second sequence for 7 consecutive days and then once-daily administration of tablets from the third sequence for 7 consecutive days. Tablets from the first sequence of Tri-Norinyl® are administered once daily for 7 consecutive days, followed by once-daily administration of tablets from the second sequence for 9 consecutive days and then once-daily administration of tablets from the third sequence for 5 consecutive days. Tablets from the first sequence of Tri-Levlen® or Triphasil® are administered once daily for 6 consecutive days, followed by once-daily administration of tablets from the second sequence for 5 consecutive days and then once-daily administration of tablets from the third sequence for 10 consecutive days. Tablets from the first sequence of Estrostep® are administered once daily for 5 consecutive days, followed by once-daily administration of tablets from the second sequence for 7 consecutive days and then once-daily administration of tablets from the third sequence for 9 consecutive days.299 The 3 sequences are then followed by a period of 7 days without drug; when a 28-day dosage preparation is used, inert tablets are administered during this latter 7-day period. Repeat dosage cycles begin on the eighth day after taking the last hormonally active tablet. If a repeat 21-day cycle is started later than the eighth day after taking the last hormonally active tablet (or later than the next day after taking the last inactive tablet with 28-day dosage preparations), a back-up method of contraception should be employed until the patient has taken a hormonally active tablet daily for 7 consecutive days.295
If oral contraceptives are first taken postpartum or later than the fifth day of the menstrual cycle, the contraceptive effect should not be relied on until after 7 consecutive days of drug administration, since there is a possibility that ovulation and conception may have occurred. In all patients, additional contraceptive measures may be advisable through the first week of the initial regimen. In determining whether to initiate oral contraceptive therapy in the postpartum period, the increased risk of thromboembolism during this period must be considered since use of oral contraceptives is also associated with an increased risk of thromboembolic and thrombotic disorders.
If spotting or breakthrough bleeding occurs during oral contraceptive use, the dosage cycle should generally be continued. Spotting or breakthrough bleeding usually stops within one week. If bleeding persists or is prolonged, nonfunctional causes should be considered.
When a woman misses one estrogen/progestin tablet of a conventional cycle oral contraceptive, the missed dose should be taken as soon as it is remembered, followed by resumption of the regular schedule. Additional contraceptive methods are not necessary if only one tablet is missed.295, 296, 298, 299, 301, 321, 332, 366 When 2 doses are missed during the first one or 2 weeks of the cycle, the 2 missed doses should both be taken as soon as they are remembered, then 2 tablets the next day, followed by resumption of the regular schedule. 295, 296, 298, 299, 301, 321 If 2 consecutive estrogen/progestin tablets are missed during the third or fourth week of a dosage cycle that was initiated on the first day of the menstrual cycle, the remainder of the tablets in the pack for that cycle should be discarded and a new dosage cycle started the same day.295, 296, 298, 299, 301, 321, 332, 366 If 2 consecutive estrogen/progestin tablets are missed during the third or fourth week of a dosage cycle that was initiated on the first Sunday on or after menstruation started, the patient should continue to take one tablet daily until Sunday, then discard the remainder of the tablets for that cycle and start a new dosage cycle that same day.295, 296, 298, 299, 301, 321, 332, 366 If 3 or more consecutive estrogen/progestin tablets are missed during a dosage cycle that was initiated on the first day of the menstrual cycle, the remainder of the tablets in that cycle should be discarded and a new dosage cycle started the same day.295, 296, 298, 299, 301, 321, 332, 366 If 3 or more consecutive estrogen/progestin tablets are missed during a dosage cycle that was initiated on the first Sunday on or after menstruation started, the patient should continue to take one tablet daily until Sunday, then discard the remainder of the tablets for that cycle and start a new dosage cycle that same day.295, 296, 298, 299, 301, 321, 332, 366 During the 28-day dosage cycle, any inactive tablets that are missed should be discarded and the patient should continue taking the remaining inactive tablets until the cycle is finished.295, 296, 298, 299, 301, 332, 366 A back-up contraceptive method is not required during the fourth week as a result of missed inactive tablets.295, 296, 298, 299, 301, 332, 366 With 28-day contraceptive cycles, a new cycle of tablets should be started the day after taking the last tablet of the previous 28-day dosage cycle (i.e., no days without tablets).295, 296, 298, 299, 301, 332, 366 If the patient is unsure of what drug regimen to take as a result of missed tablets, a back-up method of contraception should be used for each sexual encounter, and one active tablet should be taken each day until the next clinician contact.295, 296, 298, 299, 301, 321, 332, 366
Missed doses may cause light bleeding or spotting or amenorrhea, and ingestion of multiple tablets to make up for those missed (i.e., 2 doses at a time) may be associated with nausea.295, 296, 298, 299, 301 If breakthrough bleeding occurs following missed doses, it will usually be transient and of no consequence. If breakthrough bleeding resembling menstruation occurs during use of monophasic (conventional cycle) fixed-combination oral contraceptives, therapy should be discontinued, the remainder of the tablets in that cycle should be discarded, and the next cycle should be started on the next Sunday.301 There is little likelihood of ovulation when one dose is missed; however, the possibility of ovulation and spotting or breakthrough bleeding increases with each missed dose. Whenever 2 or more doses are missed, additional contraceptive methods should be used for the next 7 days.
In nonlactating postpartum women, oral contraceptives may be initiated no earlier than 28 days after delivery. In women who choose to breast-feed, oral contraceptives should not be given in the immediate postpartum period. Whenever possible, the use of oral contraceptives should be deferred until the infant has been weaned.
Extended-cycle Oral Contraceptives
When a fixed-combination extended-cycle oral contraceptive (e.g., LoSeasonique®, Seasonale®, Seasonique®) is used, the oral contraceptive is administered in a cyclic regimen using a 91-day cycle.322, 331, 354 Because extended-cycle oral contraceptives are administered using a 91-day cycle, women using these preparations should expect to have 4 menstrual periods per year.322, 331, 354 When an extended-cycle preparation is used, tablets containing estrogen/progestin are administered once daily for 84 days followed by administration of inert tablets or tablets containing 10 mcg of estrogen for 7 days.322, 331, 354 Administration of the extended-cycle preparation usually begins on the first Sunday after or on which bleeding begins.322, 331, 354 A back-up method of contraception (e.g., condom, spermicide) should be employed for 7 days following initiation of therapy.322, 331, 354 Withdrawal bleeding usually occurs during the 7 days after the last estrogen/progestin tablet.322, 331, 354 Repeat dosage cycles begin on the same day of the week (Sunday) as the initial cycle.322, 331, 354 If a repeat cycle is started later than the scheduled day, a back-up method of contraception should be employed until the patient has taken a hormonally active tablet daily for 7 consecutive days.322, 331, 354
When a woman misses one estrogen/progestin tablet of an extended-cycle oral contraceptive (i.e., LoSeasonique®, Seasonale®, Seasonique®), the missed dose should be taken as soon as it is remembered, followed by resumption of the regular schedule.322, 331, 354 Additional contraceptive measures are not necessary if only one tablet is missed.322, 331, 354 When 2 estrogen/progestin tablets are missed, the 2 missed tablets should be taken as soon as they are remembered, then 2 tablets the next day, followed by resumption of the regular cycle.322, 331, 354 A back-up method of contraception (e.g., condom, spermicide) should be employed until the patient has taken an estrogen/progestin tablet daily for 7 consecutive days.322, 331, 354 When 3 or more consecutive estrogen/progestin tablets are missed, the patient should continue to take one tablet daily; the missed tablets should be discarded.322, 331, 354 A back-up method of contraception (e.g., condom, spermicide) should be employed when the patient misses a dose and until the patient has taken an estrogen/progestin tablet daily for 7 consecutive days.322, 331, 354 Inert tablets or estrogen-containing tablets that are missed should be discarded and the patient should continue taking the remaining tablets until the cycle is finished.322, 331, 354 A back-up contraceptive method is not required if the patient missed inert or estrogen-containing tablets.322, 331, 354 If the patient is unsure of what drug regimen to take as a result of missed tablets, a back-up method of contraception should be used for each sexual encounter, and one tablet taken each day until the next clinician contact.322, 331, 354 Missed doses may cause light bleeding or spotting, and ingestion of multiple tablets to make up for those missed doses may be associated with nausea. 322, 331
In nonlactating postpartum women, fixed-combination extended-cycle oral contraceptives may be started no earlier than 28 days after delivery.322, 331, 354 Women may start taking fixed-combination extended-cycle oral contraceptives immediately following a complete first-trimester abortion; a back-up method of contraception is not needed.322, 331
Continuous-Regimen (Noncyclic) Oral Contraceptive
When a fixed-combination continuous-regimen oral contraceptive (i.e., Lybrel®) is used, the oral contraceptive is administered each day and continued daily without interruption (i.e., without a drug-free interval).339 Therefore, women using this preparation should expect no withdrawal menstruation-like bleeding; uterine bleeding and/or spotting does occur in some women.339, 340 Administration of the continuous-regimen oral contraceptive usually begins on the first day of the menstrual cycle in women who did not use hormonal contraception in the preceding month.339 A back-up method of contraception is not needed if the oral contraceptive is started on the first day of the menstrual cycle.339 The manufacturer states that women switching from a cyclic estrogen-progestin oral contraceptive should start the continuous-regimen oral contraceptive on the first day of withdrawal bleeding, within 7 days of the last hormonally active tablet; a back-up method of contraception is not needed.339 Women switching from progestin-only oral contraceptives should start the continuous-regimen oral contraceptive on the day after the last dose of the progestin-only oral contraceptive.339 Women switching from a progestin-only implant should start the continuous-regimen oral contraceptive on the same day that the implant is removed.339 Women switching from a progestin-only contraceptive injection should start the continuous-regimen oral contraceptive on the day that the next contraceptive injection would have been due.339 A back-up method of contraception (e.g., condom, spermicide) is recommended in all women switching from progestin-only contraceptives until the fixed-combination continuous-regimen oral contraceptive has been used for 7 days.339
When a woman misses one tablet of the fixed-combination continuous-regimen oral contraceptive (i.e., Lybrel®), the missed dose should be taken as soon as it is remembered, followed by resumption of the regular schedule (this may involve taking 2 tablets on one day).339 When 2 tablets are missed and the missed doses are remembered on the day of the second missed dose, the 2 missed tablets should be taken as soon as they are remembered, followed by resumption of the regular schedule.339 When 2 tablets are missed and the missed doses are remembered on the day after the second missed dose, the 2 missed tablets should be taken as soon as they are remembered, then 2 tablets the next day, followed by resumption of the regular schedule.339 When 3 or more tablets are missed, the patient should contact her clinician for advice and continue to take one tablet daily until the clinician is contacted.339 When one or more tablets are missed, a back-up method of contraception (e.g., condom, spermicide) should be used until the patient has taken the oral contraceptive for 7 days.339 If the patient is unsure of what drug regimen to take as a result of missed tablets, a back-up method of contraception should be used for each sexual encounter.339
In nonlactating postpartum women, the fixed-combination continuous-regimen oral contraceptive may be started no earlier than 28 days after delivery.339 In addition, the continuous regimen oral contraceptive may be started no earlier than 28 days after a second-trimester abortion.339 A back-up method of contraception should be used until the patient has taken the oral contraceptive for 7 days.339 Women may start the continuous-regimen oral contraceptive immediately following a complete first-trimester abortion; a back-up method of contraception is not needed.339
Each vaginal contraceptive ring containing ethinyl estradiol and etonogestrel (NuvaRing®) is intended to be used for one cycle which consists of a 3-week period of continuous use of the ring followed by a 1-week ring-free period.309 When the vaginal ring is used for contraception, one ring (delivering ethinyl estradiol 0.015 mg/24 hours and etonogestrel 0.12 mg/24 hours) is inserted into the vagina at the beginning of the cycle.309 After 3 weeks, the vaginal ring is removed on the same day of the week as it was inserted and at about the same time of day.309 After a 1-week ring-free period, a new ring is inserted on the same day of the week as in the previous cycle.309 Withdrawal bleeding usually occurs within 2-3 days after removal of the ring.309 For contraceptive effectiveness, a new ring must be inserted 1 week after the previous ring was removed even if menstrual bleeding is not finished.309
To initiate therapy, the vaginal ring (containing ethinyl estradiol and etonogestrel) usually is inserted on or before day 5 of the cycle (the first day of bleeding is counted as the first day of the menstrual cycle) in women who did not use hormonal contraception in the preceding month.309 During the first cycle, a back-up method of contraception (e.g., condom, spermicide) is recommended until the contraceptive ring has been used continuously for 7 days.309 The manufacturer states that women switching from estrogen-progestin oral contraceptives to the vaginal ring should insert the ring within 7 days of the last hormonally active tablet and no later than the day that a new oral contraceptive cycle would have been started; a back-up method of contraception is not needed.309 Women switching from progestin-only contraceptives to the vaginal ring should insert the ring on any day of the month if they are switching from a progestin-only oral contraceptive (without skipping any day between receiving the last progestin oral contraceptive and the initial administration of the vaginal ring).309 In addition, women switching from a progestin-only contraceptive injection should insert the vaginal ring on the same day as the next contraceptive injection would have been due.309 Women who are switching from a progestin-only implant or a progestin-containing intrauterine device should insert the vaginal ring on the same day as the implant or the intrauterine device is removed.309 A back-up method of contraception is recommended in all women switching from progestin-only contraceptives until the vaginal ring has been used continuously for 7 days.309
When the woman forgets to insert a new vaginal ring at the start of any cycle, the ring should be inserted as soon as she remembers and back-up contraception must be employed until the ring has been used continuously for 7 days.309 If the vaginal ring is left in place for up to 1 extra week (up to 4 weeks total), the ring should be removed and a new ring can be inserted after a 1-week drug-free interval.309 If the ring is left in place for longer than 4 weeks, pregnancy should be ruled out and a back-up method of contraception must be used until a new ring has been used continuously for 7 days.309
Women may start using the vaginal contraceptive ring in the first 5 days following a complete first-trimester abortion; a back-up method of contraception is not needed in these women.309 If the contraceptive preparation is not used within the mentioned 5 days, the woman should follow the general instructions for women who did not use hormonal contraception in the preceding month.309
If a nonlactating woman chooses to initiate contraception postpartum with the contraceptive vaginal ring (NuvaRing®) before menstruation has started, the possibility that ovulation and conception may have occurred prior to initiation of contraceptive therapy should be considered, and back-up contraception must be employed for the first 7 days.309
When the transdermal system containing ethinyl estradiol and norelgestromin (Ortho Evra®) is used for contraception, it is applied topically in a cyclic regimen using a 28-day cycle.308 One transdermal system (containing ethinyl estradiol 0.75 mg and norelgestromin 6 mg) is applied once weekly (same day each week) for 3 weeks, followed by a 1-week drug-free interval (drug-free interval should not exceed 7 days); then the regimen is repeated.309 Systemic exposure to estrogen is greater with the transdermal system (Ortho Evra®) than with oral contraceptive preparations because of differences in the pharmacokinetic profiles of the preparations.308
Administration of the transdermal contraceptive system usually begins on the first day of the menstrual cycle or on the first Sunday after menstrual bleeding has started.308 A back-up method of contraception (condom, spermicide, diaphragm) should be employed for the first 7 days after application of the first system if therapy is started after day 1 of the menstrual cycle.308 A back-up method of contraception is not needed if the first system is applied on the first day of the menstrual cycle.308 The manufacturer states that women switching from estrogen-progestin oral contraceptives to the estrogen-progestin transdermal system should apply the transdermal system on the first day of withdrawal bleeding.308 If there is no withdrawal bleeding within 5 days of the last hormonally active tablet, pregnancy must be ruled out.309 If therapy with the transdermal system is initiated after the first day of bleeding, a back-up method of contraception should be used for 7 days.308 If more than 7 days elapse after receiving the last hormonally active tablet, the possibility of ovulation and conception should be considered.309
When a woman has not adhered to the prescribed transdermal contraceptive regimen by not applying the estrogen and progestin-containing system at the initiation of any cycle (i.e., day 1/first week), the system should be applied as soon as it is remembered and a new dosage cycle started the same day; back-up contraception must be employed for the first 7 days of the new cycle.308 In addition, if the transdermal system has not been changed in the middle of the cycle (i.e., on day 8/week 2 or day 15/week 3) for 1-2 days (up to 48 hours), a new system should be applied as soon as it is remembered and the application schedule employed should be continued; back-up contraception is not needed.308 However, if the transdermal system has not been changed for more than 2 days (48 hours or more) in the middle of the cycle, a new dosage cycle should be started; back-up contraception must be employed for the first 7 days of the new cycle.308 When the transdermal system is not removed at the end of the application schedule (i.e., on day 22/week 4), the system should be removed as soon as it is remembered and the application schedule employed should be continued (i.e., system applied on day 28); back-up contraception is not needed.308
Women may start using the transdermal contraceptive system immediately after a first-trimester abortion; a back-up method of contraception is not needed.308 If the contraceptive preparation is not used within 5 days of a first-trimester abortion, the woman should follow instructions as if initiating transdermal contraception for the first time.308
Several regimens employing short-course, high-dose oral combinations of ethinyl estradiol and norgestrel or levonorgestrel have been used safely and effectively for postcoital contraception†.254, 255, 257, 258, 259, 261, 262, 264, 265 One widely studied and used regimen (the “Yuzpe” regimen) consists of an oral dose of 100 mcg of ethinyl estradiol and 1 mg of norgestrel (administered as 2 tablets each containing 50 mcg and 0.5 mg of the drugs, respectively) within 72 hours after unprotected intercourse, initiating the first dose at a time when it would make convenient administering the subsequent repeat dose 12 hours later.254, 255, 257, 258, 259, 261, 262, 264, 265, 275, 282, 284, 345 Alternative combination regimens that have been used consist of a dose of 120 mcg of ethinyl estradiol and 1.2 mg of norgestrel or 0.5-0.6 mg of levonorgestrel (e.g., administered as 4 tablets each containing 30 mcg of ethinyl estradiol and 0.3 mg of norgestrel or 0.125-0.15 mg of levonorgestrel) within 72 hours after intercourse, repeating the dose 12 hours later.264, 265, 275, 282, 284, 345 Another combination regimen that has been used consists of a dose of 100 mcg of ethinyl estradiol and 0.5 mg of levonorgestrel (e.g., administered as 5 tablets each containing 20 mcg of ethinyl estradiol and 0.1 mg of levonorgestrel) within 72 hours after intercourse, repeating the dose 12 hours later.345 Because postcoital efficacy diminishes as the time between intercourse and initiation of estrogen-progestin combination therapy increases,254, 261, 275, 282, 284, 345, 346, 347 such therapy should be initiated as soon as possible but preferably within 72 hours following unprotected intercourse.345, 346, 347 If necessary, the first dose can be given up to 120 hours after unprotected intercourse.345, 346, 347 Women should be advised that taking more than the prescribed dose probably will not further decrease the risk of pregnancy, but will increase the risk of severe adverse GI effects.265, 284, 285
If women are given a conventional mnemonic package of an oral estrogen-progestin combination for use in taking a postcoital contraceptive regimen, they should be instructed carefully regarding the number and color of the tablets to be taken with each dose and that only a portion of the contents of the package actually will be used.265
Estrogen-progestin combination formulation [brand name] | Number and color of tablets per dosea |
|---|---|
Ethinyl estradiol (50 mcg) with norgestrel (0.5 mg) [Ovral®] | 2 white tablets (any of 21 tablets) |
Ethinyl estradiol (50 mcg) with norgestrel (0.5 mg) [Ovral®-28] | 2 white tablets (any of first 21 tablets) |
Ethinyl estradiol (30 mcg) with norgestrel (0.3 mg) [Lo-Ovral®] | 4 white tablets (any of 21 tablets) |
Ethinyl estradiol (30 mcg) with norgestrel (0.3 mg) [Lo-Ovral®-28] | 4 white tablets (any of first 21 tablets) |
Ethinyl estradiol (30 mcg) with levonorgestrel (0.15 mg) [Nordette®] | 4 light-orange tablets (any of 21 tablets) |
Ethinyl estradiol (30 mcg) with levonorgestrel (0.15 mg) [Nordette®-28] | 4 light-orange tablets (any of first 21 tablets) |
Ethinyl estradiol (30 mcg) with levonorgestrel (0.15 mg) [Levlen® 21] | 4 light-orange tablets (any of 21 tablets) |
Ethinyl estradiol (30 mcg) with levonorgestrel (0.15 mg) [Levlen® 28] | 4 light-orange tablets (any of first 21 tablets) |
Ethinyl estradiol (30 mcg) with levonorgestrel (0.125 mg) [Tri-Levlen® 21] | 4 yellow tablets (any of last 10 tablets) |
Ethinyl estradiol (30 mcg) with levonorgestrel (0.125 mg) [Tri-Levlen® 28] | 4 yellow tablets (any of tablets 12-21) |
Ethinyl estradiol (30 mcg) with levonorgestrel (0.125 mg) [Tri-Phasil® 21] | 4 yellow tablets (any of last 10 tablets) |
Ethinyl estradiol (30 mcg) with levonorgestrel (0.125 mg) [Tri-Levlen® 28] | 4 yellow tablets (any of tablets 12-21) |
Ethinyl estradiol (20 mcg) with levonorgestrel (0.1 mg) [Lessina® 28] | 5 pink tablets (any of first 21 tablets) |
aDose is administered initially and then repeated 12 hours later
Contraception and Folate Supplementation
For increasing folate concentrations in women using oral contraceptives, the combination of ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg and levomefolate calcium 0.451 mg (Beyaz®) or ethinyl estradiol 30 mcg in fixed combination with drospirenone 3 mg and levomefolate calcium 0.451 mg (Safyral®) is used in the same dosage and administration (i.e., timing of initiation of therapy) as used in contraception.366, 367
For the treatment of acne vulgaris, the triphasic oral estrogen-progestin combination of ethinyl estradiol 35 mcg in fixed combination with norgestimate 0.18, 0.215, or 0.25 mg (Ortho-Tri-Cyclen®) or norethindrone 1 mg in fixed combination with ethinyl estradiol 20, 30, or 35 mcg (Estrostep®) is used in the same dosage and administration (i.e., timing of initiation of therapy) as used in contraception.
For the treatment of acne vulgaris, the estrogen-progestin combination of ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg (Yaz®) or ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg and levomefolate calcium 0.451 mg (Beyaz®) is used in the same dosage and administration (i.e., timing of initiation of therapy) as used in contraception.366, 367
Premenstrual Dysphoric Disorder
For the treatment of premenstrual dysphoric disorder, the combination of ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg (Yaz®) or ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg and levomefolate calcium 0.451 mg (Beyaz®) is used in the same dosage and administration (i.e., timing of initiation of therapy) as used in contraception.366, 367
The potential risks of estrogen-progestin contraceptive use have been established in women of reproductive age.285, 308, 309 The risks should be identical for postpubertal adolescents under 16 years of age and users 16 years of age or older.285, 308, 309, 339 Estrogen-progestin combination contraceptives including short-term, high-dose postcoital contraceptives are not indicated before menarche.285, 308, 309
Exposure to ethinyl estradiol and norelgestromin is higher in women receiving the Ortho-Evra® transdermal system than in women receiving an oral contraceptive preparation containing ethinyl estradiol 35 mcg and norgestimate 0.25 mg per tablet.308 Increased exposure to estrogen may increase the risk for adverse effects.308
Exposure to ethinyl estradiol and levonorgestrel is higher in women receiving Lybrel® (a fixed-combination continuous-regimen oral contraceptive) than in women receiving a conventional-cycle oral contraceptive containing the same ethinyl estradiol dose and a similar dose of the progestin component; use of Lybrel® results in 13 additional weeks of hormone intake per year.339
Epidemiologic data are not available to determine whether safety and efficacy associated with the vaginal route of administration of estrogen-progestin contraceptives differ from the oral route.309 Adverse effects similar to those with oral estrogen-progestin contraceptives generally are expected with vaginal estrogen-progestin contraceptives.309
Information on the potential risks of estrogen-progestin contraceptive use (and associated cautions, precautions, and contraindications) is based principally on studies and experience with preparations that contained higher estrogen and/or progestin doses than those in currently available preparations. The relative risks associated with use of currently available lower-dose preparations remains to be determined. For example, while previous experience indicated that the risk of adverse cardiovascular effects associated with oral contraceptives was increased in nonsmoking women older than 40 years of age, this risk may have resulted in part from the high estrogen content of previously available preparations. It currently is not known whether such increased cardiovascular risk also is associated with use of currently available, low-dose preparations, but some experts consider the possible benefits of low-dose (containing no more than 35 mcg of estrogen) oral contraceptives to outweigh the potential risks of pregnancy in healthy nonsmoking women older than 40 years of age who have no other risk factors. The risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other risk factors (e.g., hypertension, hyperlipidemias, obesity, diabetes).
Common adverse effects of oral estrogen-progestin contraceptives appear to be mainly caused by the estrogen, are usually most pronounced during the first oral contraceptive cycle, and disappear or diminish after 3 or 4 cycles; there does not appear to be any advantage in changing preparations during this period of time. If minor adverse effects persist after the fourth cycle, a different combination of drugs or a different dosage may be tried. Although conventional-dosage preparations (containing 35 mcg or more of ethinyl estradiol or 50 mcg or more of mestranol) are generally associated with slightly lower pregnancy rates than reduced-dosage preparations, conventional-dosage preparations are generally more frequently associated with adverse effects (e.g., edema, nausea and vomiting, thromboembolic disorders) than reduced-dosage preparations; however, reduced-dosage preparations are more frequently associated with bleeding irregularities, including breakthrough bleeding, spotting, and menstrual irregularities, than conventional-dosage preparations. Because of the increased risk of thromboembolic disorders associated with conventional-dosage preparations, reduced-dosage preparations are recommended for initial use in patients who have not previously received oral contraceptives. Although numerous adverse effects have been reported in women receiving oral contraceptives, many of the reported effects are conditions that could occur spontaneously in women of childbearing age and a causal relationship has, in many instances, been difficult to establish.
It is not known if oral contraceptive combinations containing desogestrel or norgestimate cause fewer androgenic effects (e.g., acne, hirsutism, weight gain) than estrogen-progestin combinations containing conventional progestins (e.g., levonorgestrel, norethindrone).251, 252 There is some evidence that oral contraceptives containing desogestrel may be associated with an increased risk of nonfatal venous thrombosis.
Limited data are available concerning the risk of using short-course, high-dose estrogen-progestin combinations for emergency contraception.282, 285, 286 No serious or long-term complications have been associated with such postcoital regimens in Europe, where experience is extensive.284, 286 In addition, some evidence indicates that emergency postcoital contraception may not compromise conventional contraception use or sexual behavior (e.g., promiscuity, sexually transmitted disease [STD] risk).324, 325, 326
The most frequent adverse effect of oral contraceptives is nausea. In addition, nausea has been reported in women using vaginal or transdermal estrogen-progestin contraceptives.308, 309, 311, 313, 317
The principal risk associated with currently recommended high-dose, postcoital estrogen-progestin combination regimens appears to be moderate to severe adverse GI effects including severe vomiting and nausea, which occur in 12-22 and 30-66%, respectively, of women receiving the short-course regimens and may limit compliance with, and effectiveness of, the regimens.255, 257, 264, 282, 285, 286 In 2 prospective, randomized studies, nausea and vomiting were less common with a high-dose postcoital progestin-only regimen (0.75 mg levonorgestrel every 12 hours for 2 doses) than with a high-dose estrogen-progestin regimen (100 mcg ethinyl estradiol and 0.5 mg levonorgestrel every 12 hours for 2 doses).287, 288
Other adverse GI effects include vomiting, abdominal cramps, abdominal pain, bloating, diarrhea, constipation, and inflammatory bowel disease.367 Gingivitis and dry socket also have been reported. Changes in appetite and changes in weight also may occur.
The most frequent dermatologic reaction to oral contraceptives is chloasma or melasma. Women who have had melasma during pregnancy appear to be most susceptible. Irregular brown macules may develop slowly on the face within 1 month to 2 years following initiation of oral contraceptive therapy. The macules fade more slowly than in melasma gravidarum and may be permanent.
Acne may improve during oral contraceptive therapy because of decreased sebum production and depression of sebaceous gland activity; however, it may increase in severity during initial therapy and may develop in some women who have not previously had acne.
Other dermatologic reactions include allergic rash, urticaria, erythema multiforme, erythema nodosum, hemorrhagic eruption, pruritus, and angioedema.367 Hirsutism and alopecia also have occurred. Herpes gestationis and porphyria cutanea have reportedly been adversely affected in women receiving oral contraceptives.
Application site reaction has occurred in women using the transdermal contraceptive system containing ethinyl estradiol and norelgestromin.308, 313, 317 The manufacturer states that if such skin irritation occurs, the transdermal system may be removed and a new patch applied to a different location until the next new application day.308
A positive association between the amount of estrogen and progestin in oral contraceptives and the risk of adverse cardiovascular effects has been observed. Adverse effects similar to those with oral combination estrogen-progestin contraceptives generally are expected with vaginal or transdermal estrogen-progestin contraceptives.308, 309
Increases in blood pressure may occur in women receiving estrogen-progestin contraceptives. Blood pressure elevations are usually minor, but clinically important hypertension may occur in some women. Some women develop hypertension within 1-3 weeks after initiation of oral contraceptive therapy and become normotensive during the part of the oral contraceptive cycle when they do not receive the drugs. In others, blood pressure increases slowly and may not reach abnormal levels for several months. Elevated blood pressure may gradually decrease or persist after the oral contraceptive is discontinued.
The risk of hypertension increases with increasing duration of oral contraceptive use and is about 2.5-3 times greater in the fifth year of continual use than in the first year. Age also is positively correlated with the risk of hypertension in oral contraceptive users, becoming substantial in women about 35 years of age and older. Women with a history of hypertension, preexisting renal disease, a history of toxemia or elevated blood pressure during pregnancy, a familial tendency toward hypertension or its consequences, or a history of excessive weight gain or fluid retention during the menstrual cycle may be at increased risk of developing elevated blood pressure during estrogen-progestin contraceptive therapy and, therefore, should be monitored closely. Even though elevated blood pressure may remain within the normal range, the clinical implications of elevations should be considered in all patients. All women, but particularly those with other risk factors for cardiovascular disease or stroke, should have blood pressure measurements before an oral contraceptive is prescribed and at regular intervals during therapy.
Oral contraceptive use is associated with an increased risk of thromboembolic and thrombotic disorders. One study has shown an increased relative risk of fatal venous thromboembolism (VTE) and several other studies have shown an increased relative risk of nonfatal VTE in oral contraceptive users. Case-controlled studies estimated that the relative risk for developing fatal or nonfatal thromboembolism (ranging in severity from superficial thrombosis to pulmonary embolism) was 3-11 times greater in oral contraceptive users than in nonusers and 1.5-6 times greater in women predisposed to venous thromboembolic disorders. However, cohort studies suggest that the overall relative risk is somewhat lower, ranging from 3 times greater for new cases to 4.5 times greater for new cases requiring hospitalization in oral contraceptive users when compared with nonusers. A prospective review failed to show increased mortality rates from cardiovascular disorders in oral contraceptive users; however, when a selected subset of this study was analyzed in a retrospective, case-controlled fashion, an increased risk of VTE was associated with oral contraceptive use. Hereditary coagulation disorders, such as factor V Leiden mutation, increase the risk of thromboembolic disease.285 The risk of thromboembolic disease from oral contraceptive use is not related to the duration of use and disappears when oral contraceptive use is discontinued.
The pharmacokinetic profile for the transdermal contraceptive system containing ethinyl estradiol and norelgestromin (Ortho Evra®) differs from the profile for oral contraceptive preparations.308 Overall exposure to ethinyl estradiol and norelgestromin is higher in women receiving Ortho Evra® than in women receiving an oral contraceptive preparation containing ethinyl estradiol 35 mcg and norgestimate 0.25 mg per tablet.308 (See Pharmacokinetics: Absorption.) Increased exposure to estrogen may increase the risk of certain adverse effects (e.g., VTE).308 The risk of VTE in women using Ortho Evra® relative to the risk in women using an oral contraceptive containing norgestimate or levonorgestrel and ethinyl estradiol 30-35 mcg has been investigated in several epidemiologic, case-controlled studies.308, 334, 351, 352, 353 In one study that used data from health care claims, current use of Ortho Evra® was not associated with an increased risk of nonfatal VTE compared with use of an oral contraceptive (odds ratio [OR] 0.9; 95% confidence interval: 0.5-1.6).308, 334 In a subsequent analysis that included an additional 17 months of data from this study, current use of Ortho Evra® was not associated with an increased risk of nonfatal VTE compared with use of an oral contraceptive (OR 1.1; 95% confidence interval: 0.6-2.1).308, 352 In another study that used claims data and chart review, current use of Ortho Evra® was associated with an increased risk of VTE compared with use of an oral contraceptive (OR 2.4; 95% confidence interval: 1.1-5.5).308, 351 Findings from another study that used claims data indicated current use of Ortho Evra® might be associated with an increased risk of idiopathic VTE compared with use of an oral contraceptive (OR 2; 95% confidence interval: 0.9-4.1).308, 353
Because the fixed-combination continuous-regimen oral contraceptive (Lybrel®) is administered daily (not cyclically), overall exposure to estrogen and progestin is higher in women receiving this preparation than in women receiving a conventional-cycle oral contraceptive containing the same dose of ethinyl estradiol and a similar dose of the progestin component.339
A review conducted by the US Food and Drug Administration (FDA) indicates that the use of oral contraceptive combinations that contain the progestins desogestrel (Desogen®, Ortho-Cept®) or gestodene (not commercially available in the US) may be associated with an increased risk of nonfatal venous thrombosis compared with oral contraceptives containing conventional progestins (e.g., levonorgestrel, norethindrone).239 This conclusion was based on interim results of 3 unpublished comparative studies (i.e., by the World Health Organization [WHO], by the Boston Drug Surveillance Program, by the European Transnational study coordinated by McGill University of Canada).239, 240, 241, 242 Interim results of these unpublished studies indicate that, while the overall risk of nonfatal venous thrombosis is lower than that reported in previous studies, estrogen-progestin combinations containing desogestrel or gestodene appear to be associated with a twofold increased risk of venous thrombosis compared with oral contraceptives containing conventional progestins.239 Some experts have recommended that estrogen-progestin combinations containing desogestrel or gestodene not be prescribed routinely for prevention of conception in women;240, 242 however, other clinicians state that further analysis of data is needed for such a recommendation.242 Although the FDA does not recommend that women currently using oral contraceptives containing desogestrel discontinue such use or switch to another estrogen-progestin combination contraceptive, the FDA states that women using an oral contraceptive containing desogestrel should be advised to discuss such use with their clinician, taking into consideration the relative risks and benefits associated with these oral contraceptives.239 It should be considered that the contraceptive vaginal ring (NuvaRing®) contains etonogestrel, the active metabolite of desogestrel; however, it is not known whether NuvaRing® is associated with an increased risk of venous thrombosis.309
Another safety review conducted by the FDA indicates that use of combination oral contraceptives containing the progestin drospirenone may be associated with an increased risk of VTE compared with that of oral contraceptives containing levonorgestrel or other progestins.364, 365, 366, 367, 368, 373 This conclusion was based on results of several epidemiologic studies (i.e., the US postapproval safety study by Ingenix, the European Active Surveillance Study [EURAS], the Long-Term Active Surveillance Study [LASS], 2 Danish cohort studies, the Dutch multiple environmental and genetic assessment of risk factors for venous thrombosis [MEGA] study, the UK General Practice Research Database [GPRD] study, the PharMetrics study, and the FDA-supported study) evaluating the risk of VTE in women using oral contraceptives containing drospirenone.357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373 These studies reported that the risk of VTE in such women ranged from no increase to a threefold increase in risk.357, 358, 359, 360, 361, 362, 365, 366, 367, 368, 369, 371, 372, 373 The FDA's safety review was prompted by results of 2 recent case-control studies that showed a twofold to threefold increased risk of VTE (including deep-vein thrombosis and pulmonary embolism) in patients receiving oral contraceptives containing drospirenone compared with those receiving oral contraceptives containing the progestin levonorgestrel.355, 356, 357, 358, 373 These 2 studies evaluated cases of idiopathic VTE occurring in women 15-44 years of age who were current users of oral contraceptives containing 30 mcg of estrogen with either drospirenone or levonorgestrel; women with risk factors for VTE were excluded from the studies.357, 358 The FDA has also reviewed data from a large US retrospective cohort study in more than 800,000 women evaluating thrombotic and thromboembolic risks (including VTE) associated with hormonal contraceptives.355, 356, 364, 369 Final results from this study suggest an increased risk of VTE (hazard ratio greater than 1) in women using oral contraceptives containing drospirenone compared with women using other hormonal contraceptives.356, 369 (See Cautions: Precautions and Contraindications.)
Given the conflicting results of the previous epidemiologic studies and the recent findings, the FDA held a joint meeting of the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee on December 8, 2011, to review the risks and benefits of such therapy and specifically discuss the risk of VTE associated with drospirenone-containing hormonal contraceptives.356, 373 The studies reviewed by the FDA did not provide consistent data for the comparative risk of thromboembolic events between oral contraceptives that contain drospirenone and those that do not.373 In addition, the studies did not account for important known and unknown patient characteristics that may influence prescribing patterns and may affect risk of VTE.373 For these reasons, the FDA states that it is unclear whether the increased risk of thromboembolic events observed in these epidemiologic studies actually resulted from use of drospirenone-containing oral contraceptives.373 At this time, the FDA has concluded that the risk of VTE may be higher for such oral contraceptives.373 The FDA will continue to communicate any new safety information as it becomes available.373
An increased risk of cerebrovascular disorders, including thrombotic and hemorrhagic stroke, also is associated with oral contraceptive use, although the risk generally is greatest in older (i.e., older than 35 years of age), hypertensive women who also smoke.365, 366, 367, 368 The use of estrogen-progestin contraceptives also is associated with an increased risk of stroke in women with other underlying risk factors.365, 366, 367, 368 Hypertension is a risk factor in both users and nonusers of oral contraceptives for both thrombotic and hemorrhagic stroke, while smoking appears to increase the risk for hemorrhagic stroke. Although cigarette smoking alone has been associated with an increased risk of cerebrovascular disorders, concomitant cigarette smoking and oral contraceptive use is associated with a greater risk of these disorders than either alone. The relative risk of thrombotic stroke has been shown to range from 3 for normotensive users of oral contraceptives to 14 for users with hypertension. The relative risk of hemorrhagic stroke is reported to be 1.2 in nonsmoking women who use oral contraceptives, 2.6 in nonusers who do not smoke, 7.6 in users who smoke, 1.8 in normotensive users, and 25.7 in users with severe hypertension. The risk also appears to be greater in older women.
An increased relative risk of myocardial infarction has been associated with oral contraceptive use. In one study, oral contraceptive use was one of several risk factors for coronary artery disease which included cigarette smoking, hypertension, hypercholesterolemia, obesity, diabetes, and preeclamptic toxemia; the risk of myocardial infarction increased as the number of risk factors for coronary artery disease increased. The relative risk of developing fatal myocardial infarction has been estimated as twice as great in oral contraceptive users who do not smoke compared with nonusers who do not smoke, as 5 times greater in oral contraceptive users who smoke compared with users who do not smoke, and about 10-12 times greater in users who smoke compared with nonusers who do not smoke; women who smoke 15 or more cigarettes daily are especially at risk. However, other data suggest that the likelihood of myocardial infarction is not increased in young women who use oral contraceptives and do not smoke or have hypertension or diabetes.
A positive association between thromboembolic disorders and estrogen dosage of oral contraceptives also exists. The progestin content of oral contraceptives also appears to contribute to the risk of thromboembolic disorders. Use of oral contraceptive combinations that contain the progestins desogestrel or gestodene (not commercially available in the US) may be associated with an increased risk of nonfatal venous thrombosis compared with use of oral contraceptives containing conventional progestins (e.g., levonorgestrel, norethindrone).239 However, desogestrel has minimal androgenic activity and there is some evidence that the risk of myocardial infarction associated with oral contraceptives is lower when the progestin has minimal androgenic activity than when the activity is greater. A relationship between the estrogen and/or progestin dosage of oral contraceptives and the risk of myocardial infarction has not been established. However, a decrease in serum high-density lipoprotein (HDL) concentration has been reported with increasing progestational activity of oral contraceptives and decreased HDL has been associated with an increased risk of ischemic heart disease.
The clinician and the woman using estrogen-progestin contraceptives should be alert to the earliest signs and symptoms of thromboembolic and thrombotic disorders (e.g., thrombophlebitis, pulmonary embolism, cerebrovascular insufficiency, coronary occlusion, retinal thrombosis, mesenteric thrombosis). Estrogen-progestin contraceptives should be discontinued immediately when any of these disorders occurs or is suspected. A two- to four-fold increased risk of postsurgery thromboembolic complications has been reported in oral contraceptive users; the risk in women predisposed to venous thromboembolic disorders is twice that in women who have no such predisposition.
Oral contraceptives may cause some degree of fluid retention and edema. Oral contraceptives should be used with caution in patients with conditions that might be aggravated by fluid retention. Premature ventricular and supraventricular complexes and other ECG abnormalities have been reported in women receiving oral contraceptives; however, a causal relationship has not been established.
Endocrine and Metabolic Effects
Endocrine function test results may be altered in patients receiving oral contraceptives. If results of endocrine function tests are abnormal, the tests should be repeated 2 months after the drug has been discontinued.
Decreased glucose tolerance has been observed in a significant percentage of patients receiving oral contraceptives. Fasting blood glucose concentrations are not altered in most patients; however, increased plasma insulin and blood pyruvate concentrations may occur. Although decreased glucose tolerance appears to be directly related to the estrogen of oral contraceptives, estrogen alone does not appear to decrease glucose tolerance and therefore this effect appears to involve both estrogenic and progestinic components. Progestins increase insulin secretion and insulin resistance, and these effects vary among different progestin agents.299, 301 Prediabetic and diabetic patients should be carefully monitored during estrogen-progestin contraceptive therapy.
Effects on Lipids and Lipoproteins
Increased concentrations of plasma triglyceride, low-density lipoproteins, and total phospholipids may occur during therapy with estrogen-progestin contraceptives. The clinical importance of these alterations in lipid and lipoprotein concentrations has not been established; however, it may be advisable to avoid use of oral contraceptives in women with elevated serum lipids. Generally, the progestin component of oral contraceptives has been shown to decrease high-density lipoprotein cholesterol (HDL-cholesterol), whereas the estrogen component has been shown to increase it; however, some newer progestins (e.g., desogestrel, norgestimate) also may increase HDL-cholesterol. Therefore, it has been suggested that the net effect of estrogen-progestin contraceptives on high-density lipoprotein cholesterol depends on the specific formulation.
The estrogenic component of estrogen-progestin contraceptives may produce elevations in thyroxine-binding globulin (TBG) resulting in elevated total circulating thyroid hormone, as measured by protein-bound iodine (PBI), thyroxine (T4) (by column and radioimmunoassay), and butanol extractable iodine. Decreased triiodothyronine (T3) resin uptake, reflecting elevated TBG, also occurs, while free T4 concentrations are unaltered. Basal metabolic rate, cholesterol concentrations, iodine-131 uptake, and the free thyroxine index remain unchanged, suggesting that thyroid function is not affected. Abnormal thyroid function test results usually return to pretreatment levels within 2-4 months after estrogen therapy is discontinued.
Other Endocrine and Metabolic Effects
Estrogen-progestin contraceptives also affect other serum proteins. Serum albumin may be increased or decreased and variable effects on immunoglobulins have been reported. Serum cholinesterase, haptoglobulins, and orosomucoid decrease; transferrin, plasminogen, α2-macroglobulin, and testosterone- and estradiol-binding globulins are increased. Estrogen-progestin contraceptive therapy causes decreased pregnanediol excretion. Ceruloplasmin elevations may give plasma a green color. Cryofibrinogenemia has also been reported. The renin substrate (angiotensinogen) concentration is increased and the aldosterone excretion rate is moderately elevated. Some patients may have hyporesponsive plasma renin activity with normal aldosterone excretion for a few weeks after oral contraceptives are discontinued. Estrogen-progestin contraceptives may cause increased serum magnesium, copper, zinc, and iron concentrations as well as total iron-binding capacity; however, the clinical importance of these increased mineral concentrations has not been determined.
Oral contraceptives may also decrease the response to the metyrapone test.
Because drospirenone has antimineralocorticoid activity, the potential exists for hyperkalemia to occur in high-risk patients (e.g., those with renal or hepatic impairment, adrenal insufficiency) receiving oral contraceptives containing this progestin.365, 366, 367, 368
Liver function test results may be altered in patients receiving oral contraceptives and if results of these tests are abnormal, they should be repeated 2 months after the drugs have been discontinued. Increased sulfobromophthalein retention occurs frequently, as a result of interference with the transfer of dye conjugates from liver cells into bile; uptake, conjugation, and storage do not appear to be affected. Less frequently, increased serum aminotransferase and alkaline phosphatase concentrations may occur. Liver function test results usually return to normal within several weeks after oral contraceptives are discontinued; occasionally, however, abnormal test results may persist for longer periods.
Cholestatic jaundice has been reported during oral contraceptive use. Cholestasis is manifested by the development of malaise, anorexia, and pruritus about 2 weeks to 2 months after the start of therapy. Occasionally, arthralgia, fever, and rash may occur. Serum bilirubin concentration may range from 3-10 mg/dL and is mostly conjugated. Women with a history of jaundice during pregnancy have an increased risk of jaundice recurrence while receiving oral contraceptives. If jaundice occurs during oral contraceptive therapy, the drugs should be discontinued. Oral contraceptives may precipitate hepatic forms of porphyria and these drugs probably should not be used by women who have a familial history of hepatic porphyrias, since the occurrence of these conditions appears to be genetically determined. Budd-Chiari syndrome has also occurred in oral contraceptive users. Many patients who develop oral contraceptive- or pregnancy-associated Budd-Chiari syndrome also may have inherited or acquired thrombophilia.323 Steroid hormones (including oral contraceptives) may be poorly metabolized in patients with hepatic dysfunction; therefore, the drugs should be administered with caution to these individuals.
Liver tumors have been associated with oral contraceptive use. Liver tumors have been benign or malignant and have occurred during short-term and long-term use of oral contraceptives. Most commonly, liver tumors are benign hepatocellular adenomas. Long-term oral contraceptive users have an estimated annual incidence of hepatocellular adenoma of 3-4 per 100,000; risk appears to increase after 4 or more years of use. In several women who developed benign hepatocellular adenomas during oral contraceptive use, these tumors regressed following discontinuance of the drugs. Although benign hepatocellular adenomas are apparently uncommon findings in oral contraceptive users, they may result in death because of their vascularity which predisposes them to rupture and massive hemorrhage. Therefore, the presence of a liver tumor should be considered in women who develop sudden severe abdominal pain or shock. Patients with liver tumors have shown variable clinical features which may make preoperative diagnosis difficult; some of these patients have had right upper quadrant masses, while most have had signs and symptoms of acute intraperitoneal hemorrhage. Routine radiologic and laboratory test evaluations may not be helpful. Liver scans may show a focal defect, and hepatic arteriography may be useful in diagnosing primary liver neoplasm. Hepatocellular carcinoma has also been reported rarely in women receiving oral contraceptives, although a causal relationship to the drugs has not been clearly established. For women using oral contraceptives for 8 or more years, several epidemiologic studies have suggested a relative risk that is up to 7-20 times that of nonusers, although the occurrence of this tumor is rare. It also has not been clearly established whether hepatic adenoma induced by oral contraceptives can differentiate into hepatic carcinoma.
Breakthrough bleeding and/or spotting (especially within the first 3 months of use), changes in menstrual flow, missed menses (during use), or amenorrhea (after use) may occur in women receiving hormonal contraceptives. Bleeding irregularities are more frequently associated with reduced-dosage preparations than with conventional-dosage preparations. Breakthrough bleeding that occurs early in the cycle generally is caused by a lack of adequate estrogenic stimulation, whereas bleeding after midcycle generally indicates progestin deficiency. Changes in the estrogen and/or progestin dose, ratio, and/or sequence may control or alleviate breakthrough bleeding. In women who develop breakthrough bleeding while receiving a biphasic oral contraceptive, switching to a triphasic oral contraceptive may control or alleviate bleeding since the progestin dose is increased after day 7 with the triphasic regimen. Once the possibility of pregnancy has been ruled out in women with missed menses (absence of withdrawal bleeding), switching to a preparation with higher estrogenic activity or dose or to a triphasic preparation (since it allows endometrial proliferation during the initial 7-day, low-dose progestin period) may be beneficial. However, the risks (e.g., adverse cardiovascular effects) associated with increased estrogen and progestin doses must be considered, and increasing the dose to minimize bleeding irregularities should only be done if necessary.
While use of an extended-cycle oral contraceptive (e.g., LoSeasonique®, Seasonale®, Seasonique®) results in fewer planned menses (4 per year) than conventional-cycle oral contraceptives (13 per year), bleeding irregularities occur more frequently in women using the extended-cycle preparation than in women using the conventional-cycle preparation.322, 331, 354 Irregular bleeding occurs most often during the first few 91-day cycles.322, 331, 354 In one study in women who had used oral contraceptives, administration of Seasonale® resulted in 7 or more and 20 or more days of intramenstrual bleeding and/or spotting in 65 and 35% of women, respectively, during cycle 1 and in 42 and 15% of women, respectively, during cycle 4.322 In another study, administration of Seasonique® resulted in 7 or more and 20 or more days of intramenstrual bleeding and/or spotting in 64 and 29% of women, respectively, during cycle 1 and in 39 and 11% of women, respectively, during cycle 4.331 In women receiving a conventional-cycle oral contraceptive, intramenstrual bleeding and/or spotting for 7 or more and 20 or more days occurred in 38 and 6% of women, respectively, during cycles 1-4 and in 39 and 4% of women, respectively, during cycles 10-13.322
Use of extended-cycle oral contraceptive preparations is associated with fewer menstrual symptoms than use of conventional-cycle oral contraceptive preparations.335, 336 Whether adding 10 mcg of estradiol to the final 7 tablets in the cycle (LoSeasonique®, Seasonique®) will further reduce withdrawal symptoms (e.g., migraine headache) remains to be determined.335
While use of a continuous-regimen (noncyclic) estrogen-progestin oral contraceptive (Lybrel®) eliminates withdrawal bleeding, irregular bleeding and/or spotting occurs in some women.339, 340 In one study, administration of Lybrel® resulted in 4 or more and 7 or more days of bleeding and/or spotting in 67 and 54% of women, respectively, during the second 28-day dosing period and in 31 and 20% of women, respectively, during the thirteenth 28-day dosing period.339
Adequate diagnostic procedures should be performed in patients with undiagnosed persistent or recurrent vaginal bleeding. When pathology has been excluded, time or change to another preparation may resolve the problem. Women with a history of oligomenorrhea or secondary amenorrhea or young women with irregular cycles may tend to remain anovulatory or to become amenorrheic after discontinuance of oral contraceptives; women with these preexisting problems should be advised of this possibility and encouraged to use other contraceptive methods.
Dysmenorrhea also may occur. Post-use anovulation, occasionally accompanied by galactorrhea, and a premenstrual-like syndrome has been reported. Post-use anovulation may be prolonged and may occur in women who had no previous irregularities. Galactorrhea and pituitary tumors (e.g., adenomas) have been associated with amenorrhea in former oral contraceptive users. One study showed a 16-fold increased prevalence of prolactin-secreting pituitary tumors (prolactinomas) among former users of oral contraceptives who had amenorrhea with galactorrhea compared with those without galactorrhea. In another study, the relative risk of prolactinoma was 1.3 when oral contraceptives were used for contraception and 7.7 when the drugs were used for menstrual regulation. In patients with breakthrough bleeding or irregular vaginal bleeding, nonfunctional causes should be considered.
Changes in cervical erosion and secretions and endocervical hyperplasia may occur during oral contraceptive therapy. In addition, preexisting uterine leiomyoma may increase in size in women receiving oral contraceptives. Vaginitis, impaired renal function, and backache and a cystitis-like syndrome have been reported but have not been definitely attributed to the drugs.
An increased incidence of Candida vaginitis has been associated with oral contraceptive therapy. Decreased motility and tonus of the upper urinary tract may occur in some patients leading to overdistention of the ureters, thus promoting bacteriuria and its complications and making treatment of the infection more difficult. Because oral contraceptives change the vaginal pH from acidic to alkaline, it has been suggested that there may be an increased risk of gonorrhea infection upon exposure; however, there is some evidence that progestins may inhibit growth of Neisseria gonorrhoeae in vitro and that oral contraceptives may have some protective effect against gonococcal pelvic inflammatory disease (PID). Although some clinicians have suggested that the risk of PID may be decreased in oral contraceptive users, there is some evidence that the frequency of cervical chlamydial infections may be increased several-fold in women receiving oral contraceptives compared with nonusers or women using barrier contraceptives, possibly secondary to cervical ectopy induced by the drugs; therefore, it should not be assumed that oral contraceptives provide protection against PID (i.e., that caused by Chlamydia trachomatis ).
Although it has been suggested (based on very limited data) that use of multiphasic estrogen-progestin oral contraceptives may be associated with an increased risk of functional ovarian cysts, there currently is insufficient evidence to determine whether such increased risk exists. Epidemiologic evidence with monophasic estrogen-progestin oral contraceptives, principally high-dose estrogen preparations, indicates that monophasic contraceptives are associated with a reduced risk of developing functional ovarian risks when compared with nonusers of oral contraceptives. Epidemiologic studies and postmarketing surveillance currently are under way to determine the incidences of ovarian cysts in users of various types of oral contraceptives and in similar women not using the drugs.
Coital problems, device expulsion, and vaginal symptoms (discomfort, vaginitis, leukorrhea, foreign body sensation) have occurred in women using the contraceptive vaginal ring containing ethinyl estradiol and etonogestrel.309, 311
Mental depression may occur in women receiving oral contraceptives. In a few cases, mental depression has been severe and has led to suicidal behavior. Mental depression appears to occur most frequently in patients with a history of depression, including premenstrual depression; however, relief of premenstrual tension occurs in some women. Patients with a history of mental depression should be observed carefully and the estrogen-progestin contraceptive discontinued if severe depression recurs during use.
Fatigue, dizziness, nervousness, aggressiveness, anxiety, emotional lability, and irritability have been reported in women receiving estrogen-progestin contraceptives; changes in libido may also occur. Psychotic behavior, chorea, and cerebrovascular disease (with associated mitral valve prolapse) have also been reported; however, a causal relationship has not been established.
Headache, especially migraine headache, may occur during estrogen-progestin contraceptive therapy. Estrogen-progestin contraceptives should be discontinued and the cause evaluated when migraine occurs or is exacerbated, or when a new headache pattern develops which is recurrent, persistent, or severe.
Oral contraceptives have been reported to produce harmful ocular effects in myopic women. In women who developed myopia at or near puberty and in whom myopia became stable in adulthood, the drugs have reportedly increased the refractive error 2- to 3-fold, usually after 6 months of use. In women who are myopic and have considerable astigmatism, oral contraceptives may produce marked changes in the astigmatic error, possibly leading to frank keratoconus. In addition, oral contraceptives may produce a rapid advancement of the ocular disorder in patients with a family history of marked myopic astigmatism or keratoconus. Contact lens wearers receiving estrogen-progestin contraceptives may have more difficulties with their contact lenses than do nonusers who wear contact lenses. Contact lens wearers who develop visual disturbances or changes in lens tolerance during estrogen-progestin contraceptive use should be assessed by an ophthalmologist; temporary or permanent cessation of contact lens wear should be considered.
Neuro-ocular lesions such as optic neuritis or retinal thrombosis have been associated with estrogen-progestin contraceptive use. If unexplained, sudden or gradual, partial or complete loss of vision; proptosis or diplopia; papilledema; or retinal vascular lesions occur during therapy with estrogen-progestin contraceptives, the drugs should be discontinued and evaluation for retinal vein thrombosis should be instituted immediately along with other appropriate diagnostic and therapeutic measures.365, 366, 367, 368 Cataracts have also occurred during oral contraceptive use but have not been directly attributed to the drugs.
Changes in various blood factors and blood components have been observed in patients receiving oral contraceptives; however, further studies are required before the clinical importance of these changes can be established. Increases in fibrinogen and blood coagulation factors II, VII, VIII, IX, X, and XII levels and decreases in antithrombin III activity may occur in women receiving hormonal contraceptives. Blood coagulation factor levels may return to normal one to several weeks after the oral contraceptive is discontinued. Hematocrit may be slightly increased and an increased rate of blood coagulation may occur. The estrogen component of the contraceptive appears to enhance norepinephrine-induced platelet aggregation, whereas the progestin causes increased fibrinolytic activity. Anemia and sickle cell disease have also been reported during oral contraceptive use.
Breast changes, including tenderness, enlargement, and secretion, may occur during estrogen-progestin contraceptive use.
Oral contraceptive use and estrogen use have appeared to be associated with an increased risk of gallbladder disease, especially in young women. In one study, an increased risk of gallbladder disease occurred after 2 years of use of the drugs and doubled after 4 or 5 years of use. In another study, an increased risk was apparent between 6-12 months of use. However, recent evidence suggests that the risk of gallbladder disease may be minimal in patients using formulations of oral contraceptives containing relatively low dosages of estrogens and/or progestins.
The relationship between oral contraceptive use and systemic lupus erythematosus (SLE) is not well-defined. Positive lupus erythematosus (LE) cell test results and antinuclear antibodies have been associated with oral contraceptive use in some women. Precipitation of SLE and exacerbation of preexisting disease have also been associated with oral contraceptive use in some women, and some clinicians recommend that other methods of contraception be used in women with a history of SLE. Rheumatic symptoms and synovitis have been associated with oral contraceptive use. Although several epidemiologic studies have suggested that oral contraceptive use appears to be associated with a decreased incidence of rheumatoid arthritis compared with nonuse, one epidemiologic study found no such association and the relationship, if any, between oral contraceptive use and rheumatoid arthritis remains to be determined.
Other reported adverse effects of estrogen-progestin contraceptives include Raynaud's phenomenon, auditory disturbances, hemolytic uremic syndrome, colitis, pancreatitis, upper respiratory tract infection, sinusitis, and rhinitis.
Precautions and Contraindications
Use of estrogen-progestin oral contraceptives is associated with an increased risk of several serious conditions including thromboembolism, arterial thrombosis (e.g., stroke, myocardial infarction), liver tumor, gallbladder disease, visual disturbances, fetal abnormalities, and hypertension.365, 366, 367, 368 The risk of thrombotic events is even higher in women with other risk factors for these events.365, 366, 367, 368 Cigarette smoking increases the risk of serious adverse cardiovascular effects during oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes daily) and is markedly greater in women older than 35 years of age. Women who are receiving estrogen-progestin contraceptives should be strongly advised not to smoke. Women older than 35 years of age who smoke, and women with ischemic heart disease or a history of this disease, should not use estrogen-progestin contraceptives. Estrogen-progestin contraceptives should be used with caution in women with cardiovascular disease risk factors.299, 301, 365, 366, 367, 368 Clinicians prescribing estrogen-progestin contraceptives should be aware of the risks associated with such use; the sections in Cautions and the manufacturers' labeling should be consulted for further discussion of these risks and associated precautions. In addition, potential noncontraceptive benefits associated with use of estrogen-progestin contraceptives can be considered.
Because of dose-related risks of vascular disease from oral contraceptives, the dosage regimen prescribed should contain the least amount of estrogen and progestin that is compatible with a low failure rate and the needs of the patient.
Adverse effects similar to those with oral combination estrogen-progestin contraceptives generally are expected with vaginal or transdermal estrogen-progestin contraceptives.308, 309
No data are available concerning the risk of using short-course, high-dose estrogen-progestin combinations for emergency contraception among women with contraindications to routine use of cyclic estrogen-progestin combinations for contraception.282, 285, 345 Since such postcoital contraceptive regimens do not appear to adversely affect clotting factors, vascular complications (e.g., abnormal blood clotting, stroke, myocardial infarction) are unlikely to occur.284, 285 No serious or long-term complications have been associated with such postcoital contraceptive regimens in Europe, where experience is extensive.284 Most experts state that there currently is no real contraindication to postcoital (emergency) contraception with the recommended regimens and that the benefits generally outweigh any theoretical or proven risk.345, 346, 350
Patients should be advised that emergency contraceptive regimens are not as effective as most other forms of long-term contraception and should not be used as a woman's routine form of contraception.285, 345, 346 Patients should be informed that as with all estrogen-progestin contraceptives and other nonbarrier contraceptive methods, emergency contraceptive regimens do not protect against human immunodeficiency virus (HIV) infection or other sexually transmitted diseases.290, 365, 366, 367, 368
Women receiving estrogen-progestin contraceptives should be under supervision of a physician who should inform them of the possible risks involved. Women receiving these contraceptives also should be given a copy of the patient labeling for the drugs.
It is good medical practice that all women, including those receiving estrogen-progestin contraceptives, have a medical history and physical examination performed annually. The physical examination may be deferred until after initiation of these contraceptives if requested by the woman and judged appropriate by the clinician. Physical examination should include special attention to blood pressure, breasts, abdomen, and pelvic organs and should include a Papanicolaou test (Pap smear) and relevant laboratory tests.
Women receiving estrogen-progestin contraceptives (including drospirenone-containing oral contraceptives) should be advised to notify their clinician if signs or symptoms of thromboembolic or thrombotic disorders (e.g., thrombophlebitis, pulmonary embolism, cerebrovascular insufficiency, coronary occlusion, retinal thrombosis, mesenteric thrombosis) occur, including sudden severe headache or vomiting, disturbance of vision or speech, sudden partial or complete loss of vision, dizziness or faintness, weakness or numbness in an extremity, sharp or crushing chest pain, unexplained cough, hemoptysis, sudden shortness of breath, calf pain, or heaviness in the chest.355, 356, 373 Oral contraceptive combinations containing drospirenone should be discontinued if an arterial or venous thrombotic event occurs during therapy.365, 366, 367, 368 Women currently receiving an oral contraceptive combination containing drospirenone should be informed of the potential risk of thromboembolic events.356, 373 Patients also should be advised about the current information available regarding the risk of VTE with oral contraceptives containing drospirenone compared with those containing levonorgestrel.356 Known risk factors for development of VTE include smoking, obesity, family history, and other factors that contraindicate the use of oral contraceptive combinations.356, 365, 366, 367, 368 Patients should discuss their risk of VTE with their clinician before deciding which contraceptive method to use.356, 364 The risk of thromboembolic disease associated with oral contraceptive use gradually disappears after such therapy is discontinued.365, 366, 367, 368 However, the FDA states that patients should not discontinue oral contraceptives containing drospirenone without consulting a clinician.355, 356, 373
Although the risk of VTE is higher in women using any oral contraceptives compared with nonusers, the risk remains lower than that associated with pregnancy and the postpartum period.373 The risk of VTE in women receiving estrogen-progestin oral contraceptives is estimated to be 3-9 per 10,000 woman-years.365, 366, 367, 368 In comparison, if 10,000 women who are not pregnant and not users of oral contraceptives are followed for one year, 1-5 of these women will develop a VTE.365, 366, 367, 368 The risk of VTE is highest during the first year of oral contraceptive use.365, 366, 367, 368, 373 Results from a large, prospective cohort safety study of various estrogen-progestin oral contraceptives suggest that this increased risk is highest during the first 6 months of use compared with that in nonusers.365, 366, 367, 368 Data from this safety study indicate that the highest risk of VTE occurs after initiation of estrogen-progestin oral contraceptive therapy or resumption of therapy (following a 4-week or longer drug-free interval) with the same or a different oral contraceptive combination.365, 366, 367, 368 Before initiating use of an estrogen-progestin combination containing drospirenone in a new user or in a woman who is switching from an oral contraceptive not containing drospirenone, clinicians should consider the risks and benefits of drospirenone-containing oral contraceptives, including risk for developing VTE, specific to that woman.356, 364, 365, 366, 367, 368, 373
Women receiving estrogen-progestin contraceptives should also be advised to inform their physician if severe abdominal pain or mass (indicating a possible liver tumor), jaundice, severe mental depression, edema, or unusual bleeding occurs.298, 299, 301 Because severe nausea and vomiting have occurred following postcoital use of high-dose estrogen-progestin combinations as emergency contraception, women taking such therapy should be instructed carefully regarding what to do if vomiting occurs after administering a dose, and concomitant use of an antiemetic should be considered.254, 255, 257, 258, 259, 260, 261, 262, 264, 265, 282, 284, 285 (See Dosage and Administration: Administration.) Women receiving estrogen-progestin contraceptives should be instructed in self-examination of their breasts and should report nodules or fibrocystic disease in the breast or abnormal breast radiographic or mammographic findings to their physician.298, 299, 301
Estrogen-progestin contraceptives should be used with caution, and only with careful monitoring, in patients with conditions that might be aggravated by fluid retention (e.g., asthma, seizure disorders, migraine, or cardiac, renal, or hepatic insufficiency) and in patients being treated for hyperlipidemia, since control of the condition may become difficult. Women with a history of hypertension, hypertension-related diseases, or renal disease should be encouraged to use another method of contraception. Women with hypertension who elect to use estrogen-progestin contraceptives should be monitored closely, and if a clinically important elevation of blood pressure occurs, use of the drugs should be discontinued.
Because a twofold to fourfold increased risk of postsurgery thromboembolic complications has been reported in oral contraceptive users, estrogen-progestin contraceptives should be discontinued whenever feasible, at least 4 weeks before surgery that is associated with an increased risk of thromboembolism or prolonged immobilization; it is also recommended that patients wait 2 weeks after elective surgery associated with an increased risk of thromboembolism or after immobilization before resuming the use of these contraceptives.365, 366, 367, 368
Although the absolute rates for developing VTE are increased for users of hormonal contraceptives compared with nonusers, the rates for VTE development are even greater during pregnancy, especially during the postpartum period.365, 366, 367, 368 Since the immediate postpartum period is associated with an increased risk of thromboembolism, estrogen-progestin contraceptive use should be started no earlier than 4 weeks after delivery in women who elect not to breastfeed their infants or in women who have had a midtrimester pregnancy termination.365, 366, 367, 368 The risk of thromboembolism decreases while the risk of ovulation increases after the first 3 weeks postpartum.365, 366, 367, 368
Oral contraceptives containing the progestin drospirenone should not be used in patients who are predisposed to developing hyperkalemia (e.g., those with renal or hepatic impairment or adrenal insufficiency).365, 366, 367, 368 If a drospirenone-containing oral contraceptive is used in women receiving daily, long-term therapy with agents that may increase serum potassium concentrations (e.g., angiotensin-converting enzyme (ACE) inhibitors, angiotensin II type 1 (AT1) receptor antagonists, potassium-sparing diuretics, heparin, aldosterone antagonists [spironolactone], nonsteroidal anti-inflammatory agents [NSAIAs]), the serum potassium concentration should be determined during the first oral contraceptive cycle.365, 366, 367, 368
Five out of the 15 pregnancies reported in large clinical trials in women using the transdermal contraceptive system containing ethinyl estradiol and norelgestromin (Ortho Evra®) occurred in women with a baseline weight of 90 kg or more; these results suggest that the contraceptive preparation may be less effective in such women than in those with a lower body weight.308 The clinician and the woman with high body weight should discuss the individual needs of such a patient when choosing an appropriate contraceptive option.308
The contraceptive vaginal ring containing ethinyl estradiol and etonogestrel (NuvaRing®) may not be suitable for women with conditions that make the vagina susceptible to vaginal irritation or ulceration.309
Estrogen-progestin contraceptives are contraindicated in women who are hypersensitive to the drug or any ingredient in the formulation and in those with known or suspected pregnancy, undiagnosed abnormal genital bleeding, diplopia or any ocular lesion arising from ophthalmic vascular disease, classical migraine, active liver disease, or history of cholestatic jaundice with pregnancy or with prior use of oral contraceptives. The drugs also are contraindicated during breast-feeding and in women who have or have had thrombophlebitis or thromboembolic disorders, cerebrovascular or coronary artery disease (including myocardial infarction), severe hypertension, diabetes with vascular involvement, known or suspected carcinoma of the breast, known or suspected estrogen-dependent neoplasia (e.g., carcinoma of the endometrium), or benign or malignant liver tumor that developed during oral contraceptive or other estrogen use. Oral contraceptives containing the progestin drospirenone are contraindicated in women with renal impairment, hepatic tumors (benign or malignant) or hepatic disease, adrenal insufficiency, high risk of arterial or venous thrombotic diseases, undiagnosed abnormal uterine bleeding, history of breast cancer or other estrogen- or progestin-sensitive cancer, and in pregnancy.365, 366, 367, 368
Safety and efficacy of estrogen-progestin contraceptives have been established in women of reproductive age.285, 295, 308, 309, 331, 332, 337, 339, 354, 365, 366, 367, 368 Safety and efficacy are expected to be identical for postpubertal adolescents under 16 years of age and users 16 years of age or older.285, 295, 331, 332, 337, 339 The manufacturers of estrogen-progestin contraceptives containing drospirenone state that safety and efficacy are expected to be the same for postpubertal adolescents under 18 years of age and users 18 years of age or older.365, 366, 367, 368 Estrogen-progestin contraceptives are not indicated before menarche.285, 295, 308, 309, 331, 332, 337, 339, 354, 365, 366, 367, 368
Oral contraceptives have not been evaluated in women 65 years of age and older and are not indicated in this population.321, 331, 332, 337, 339, 354, 365, 366, 367, 368
Mutagenicity and Carcinogenicity
Chromosomal abnormalities determined in peripheral lymphocytes have been increased in women receiving oral contraceptives compared with nonusers.201
Prolonged continuous administration of natural or synthetic estrogen in certain animal species increases the frequency of certain benign or malignant tumors including those of the breast, cervix, uterus, vagina, ovary, pituitary, and liver. Certain synthetic progestins (none currently contained in oral contraceptives) have increased the frequency of benign and malignant mammary nodules in dogs. Drospirenone has increased the frequency of benign and total (benign plus malignant) adrenal gland pheochromocytomas in rats and the frequency of carcinomas of the harderian gland in mice.365, 366, 367, 368
The manufacturers state that there is at present no consistent evidence from human studies of an increased risk of cancer associated with oral contraceptive use; whether this statement also applies to vaginal or transdermal estrogen-progestin contraceptives is not known.308, 309 Close clinical surveillance of all women using estrogen-progestin contraceptives is, nevertheless, essential. Appropriate diagnostic measures should be undertaken to rule out malignancy in all women with undiagnosed persistent or recurrent abnormal vaginal bleeding. Women with a strong family history of breast cancer or who have breast nodules, fibrocystic disease, or abnormal mammographic findings should be closely monitored if they elect to use estrogen-progestin contraceptives.
There is some evidence from epidemiologic studies that use of oral contraceptives may be associated with an increased risk of cervical carcinoma. In one study, the incidence of biopsy-proven cervical neoplasia (i.e., dysplasia, carcinoma in situ , or invasive carcinoma) was increased in long-term oral contraceptive users compared with women who used an intrauterine contraceptive device (IUD); it was recommended that particular attention to the importance of regular Papanicolaou tests be given in women who have used oral contraceptives for longer than 48 months. Although a causal relationship to the drugs could not be excluded, data from a population-based (Costa Rican women), case-control study suggest that the increased risk of carcinoma in situ associated with oral contraceptive use may have resulted from a detection bias secondary to more frequent use of Papanicolaou tests in oral contraceptive users.231 These data revealed no evidence of increased risk of invasive cervical cancer in users compared with nonusers.231 The FDA recommends that all estrogen-progestin contraceptive users be monitored carefully with physical examinations and Papanicolaou tests, at least yearly.
Several retrospective case-controlled studies have shown an increased relative risk of endometrial carcinoma in postmenopausal women who received prolonged estrogen replacement therapy for relief of menopausal symptoms. Although an increased risk of adenocarcinoma of the endometrium has been associated with sequential oral contraceptive use (sequential oral contraceptives are no longer available in the US), no association between increased risk of endometrial cancer and use of currently available estrogen-progestin combination preparations or progestin-only preparations has been shown, although individual cases have been reported. The Cancer and Steroid Hormone Study of the US Centers for Disease Control and Prevention (CDC) and the National Institute of Child Health and Human Development (NICHD) showed that women who used estrogen-progestin oral contraceptives had decreased relative risk of epithelial endometrial cancer (i.e., adenocarcinoma, adenoacanthoma, and adenosquamous cancers) compared with nonusers; the protective effect occurred in women who had used combination oral contraceptives for at least 12 months, and it persisted for at least 15 years after discontinuance of oral contraceptives.220 This decreased risk of endometrial cancer was not evident in women who had used oral contraceptives for less than 12 months.220
Several studies have shown a decreased risk of epithelial ovarian cancer in oral contraceptive users compared with nonusers. The Cancer and Steroid Hormone Study showed that women who used oral contraceptives had a decreased relative risk of epithelial ovarian cancer compared with nonusers; the protective effect occurred in women who had used oral contraceptives for as little as 3-6 months, and it persisted for at least 15 years after discontinuance of oral contraceptive use.221 The risk of ovarian cancer decreased with increasing duration of oral contraceptive use and did not appear to be affected by the age at the time of first use of oral contraceptives or the oral contraceptive type (i.e., combination or sequential) or specific formulation.221 Because of inadequate data, the association between use of oral contraceptives and nonepithelial (i.e., germ-cell, sex cord-stromal) ovarian cancers could not be fully assessed.221
Many studies have shown no increased risk of breast cancer in women receiving oral contraceptives or estrogens.318 Some studies, however, have suggested an overall increased risk of breast cancer in women receiving oral contraceptives223 and some studies have suggested that certain subgroups of women who use oral contraceptives may be at increased risk (e.g., women younger than 45 years of age who have used oral contraceptives, women who begin oral contraceptive use early in their childbearing years, women who use oral contraceptives for extended periods of time, women who use oral contraceptives before a first full-term pregnancy);223, 224, 225, 228, 229, 230 however, these findings have occurred in only some studies and other large studies have shown no such possible associations.318, 319, 230 Because of several studies suggesting an increased risk of breast cancer with oral contraceptive use, the FDA Fertility and Maternal Health Drugs Advisory Committee reviewed these data in early 1989.230 The Committee concluded at that time that existing data suggested no overall increased risk of breast cancer associated with oral contraceptive use and that a change in prescribing practices by clinicians or in the use of oral contraceptives by women was not justified.230
The Cancer and Steroid Hormone (CASH) study showed no association between oral contraceptive use and the risk of breast cancer; the duration of oral contraceptive use, time since first use, or menopause status did not alter the user's risk of breast cancer.202, 205 In addition, in the CASH study, oral contraceptive use before a woman's first full-term pregnancy did not increase her risk of breast cancer compared with other methods of delaying first pregnancy.202 In a population based, case-controlled (Women's CARE) study in women 35-64 years of age, current or former use of oral contraceptives was not associated with an increased risk of breast cancer.318, 319 Findings from the Women's CARE study generally are in agreement with results from the Cancer and Steroid Hormone Study.319 In the Women's CARE study, the relative risk of breast cancer did not increase consistently with longer periods of use or higher dosages of estrogen, nor was the risk increased with initiation of oral contraceptives at young age or in those with history of breast cancer in a first-degree relative.318, 319 There was no consistent difference in risk between white and black women.318, 319 The age at last use, use in relation to the first term pregnancy, duration of use before the first term pregnancy, or type of progestin did not change the oral contraceptive user's risk of breast cancer.318 A case-control study by the University of Southern California Cancer Surveillance Program indicated that use of “high-progestin” combination oral contraceptives (relative progestin potency determined by delay in menses test) before 25 years of age was associated with an increased risk of breast cancer;225 however, the validity of this study has been questioned and the CASH study found no such association.226, 227 In this latter study, neither the type of estrogen nor the type of progestin contained in oral contraceptives was associated with increased risk of breast cancer; 202 the type of progestin also was not associated with an increased risk of breast cancer in the Women's CARE study.318 In these studies, the type of oral contraceptive used (i.e., combination, sequential, progestin only, or more than one type) did not increase the risk.202, 318 Another case-control study indicated that in women younger than 45 years of age use of oral contraceptives before their first full-term pregnancy was associated with an increased risk of breast cancer;228 the CASH study and the Women's CARE study found no such association.202, 310 In a meta-analysis of numerous clinical trials, a small increase in the frequency of breast cancer localized to the breast was diagnosed in women within 10 years of current or past use of combined estrogen-progestin oral contraceptives.300, 320 The Women's CARE study found no such association.318 No increase in the frequency of breast cancer was diagnosed in women who had not received estrogen-progestin combination oral contraception for at least 10 years.300
While the relationship between breast cancer risk and use of oral contraceptives in women with a familial predisposition to breast cancer has not been precisely established, results from a multigenerational study suggest that women who used earlier formulations of oral contraceptives (i.e., high-dose formulations commercially available prior to 1975) and who also have a first-degree relative with breast cancer may be at increased risk of breast cancer.292, 293 This multigenerational, historical cohort study included the relatives (i.e., daughters, sisters, granddaughters, nieces, women who married into the families) of over 400 women diagnosed with breast cancer between 1944 and 1952 (probands).292, 293 In the entire cohort (i.e., daughters, sisters, granddaughters, nieces, women who married into the families), the relative risk (RR) of breast cancer was 1.4 in those who reported ever having used oral contraceptives.292 Risk was not influenced by duration of contraceptive use.292 After accounting for age and birth cohort, use of oral contraceptives was associated with an increased risk of breast cancer (RR of 3.3) among sisters and daughters of the probands but not among their nieces or granddaughters (RR of 1.2) or in women who married into the family (RR of 1.2).292, 293 The risk to first-degree relatives increased with the number of relatives in the family with breast or ovarian cancer; the relative risk was 4.6 for families with at least 3 members who had breast or ovarian cancer and 11.4 for families with at least 5 members who had breast or ovarian cancer.292, 293 The risk of breast cancer was not increased in first-degree relatives who reported use of oral contraceptives after 1975, although the small number of reported cases of cancer in this study (2 of 60 women who took oral contraceptives) limits the statistical reliability of this finding.292, 293 While the increased risk of breast cancer among high-risk women in this study appeared to be limited to those who used earlier formulations containing higher dosages of estrogen and progestin than current oral contraceptives, the mean age for first-degree relatives who reported use of oral contraceptives after 1975 was 43 years, and breast cancer may not yet have occurred in many women in this group.292, 293 The Women's CARE study found no association between use of oral combination contraceptives with high dose estrogen (50 mcg or more of ethinyl estradiol or 75 mcg or more of mestranol) and an increased risk of breast cancer in women with a family history of breast cancer.318 The relative risk of breast cancer in women with a family history of breast cancer who received high dose estrogen combinations for up to 15 years or longer was essentially the same as the relative risk in women with a family history of breast cancer who received lower-dose estrogen combinations for similar periods of time.318, 292
Although an increased occurrence of malignant melanoma, urinary tract cancers, and thyroid cancers has been reportedly associated with oral contraceptive use, these findings have not been established. Although liver tumors (mainly hepatocellular adenomas) have been associated with oral contraceptive use, these liver tumors have usually been benign.
Pregnancy, Fertility, and Lactation
Although preliminary evidence suggested that oral contraceptives could cause serious fetal toxicity when administered to pregnant women, current evidence does not suggest an association between inadvertent use of oral contraceptives in early pregnancy and teratogenic effects (including cardiovascular and limb defects, which have been reported following use of sex hormones). In addition, extensive epidemiologic studies have revealed no increased risk of birth defects in neonates born to women who used estrogen-progestin contraceptives prior to pregnancy. However, since the risks of estrogen-progestin contraceptive use clearly outweigh any possible benefit in women who are pregnant, these agents are contraindicated in such women. Although estrogens and/or progestins were previously used to treat threatened or habitual abortion, there is considerable evidence that estrogens are ineffective and no evidence from well-controlled studies that progestins are effective for these uses. Progestin-only or estrogen-progestin contraceptives should not be used to induce withdrawal bleeding as a test of pregnancy.
Data concerning pregnancy outcomes following unsuccessful emergency postcoital contraception with estrogen-progestin combinations are limited, in part because such women may choose abortion following failure of postcoital contraception.255, 260 Pooled data from several controlled trials that followed pregnancies that occurred despite postcoital estrogen-progestin combinations indicate delivery of 45 healthy neonates, 1 neonate with absent left kidney, and 2 neonates with minor anomalies.255, 260, 282 In addition, numerous studies evaluating teratologic risk of conception during cyclic (routine) oral contraceptive regimens (for both currently available low-dose oral contraceptive regimens and older, high-dose preparations [e.g., 150 mcg of ethinyl estradiol daily] that are no longer available) indicate no increased fetal risks.265, 283, 284, 285, 286 Exposure to the amount of estrogen-progestin in postcoital contraceptive regimens is not large when compared with the total amount of the estrogen-progestin cyclic (routine) oral contraceptive regimens,284 and there currently is no evidence of substantial risk to the fetus with such short-term exposure.265, 284, 286 Estrogen-progestin postcoital contraceptive regimens are contraindicated in pregnancy because of lack of efficacy, not because of adverse effects on the fetus.285, 286
In women who have missed 2 consecutive menstrual periods during estrogen-progestin conventional-cycle contraceptive use, the drug should be withheld until pregnancy has been ruled out. In women using a fixed-combination extended-cycle oral contraceptive (e.g., LoSeasonique®, Seasonale®, Seasonique®), the possibility of pregnancy should be considered after one missed menstrual period.322, 331, 354 When the woman has not adhered to the prescribed oral contraceptive regimen, the possibility of pregnancy should be considered after one missed menstrual period and the drug should be withheld until pregnancy has been ruled out. A back-up method of contraception should be instituted until the possibility of pregnancy has been eliminated.301 If pregnancy is confirmed, the woman should be informed of the potential hazard to the fetus and the advisability of continuing the pregnancy should be weighed against the risks of exposure of the fetus to the drugs.
Studies have found a slight delay in return to fertility but no absolute impairment of fertility following discontinuance of fixed-combination conventional-cycle oral contraceptives.342, 343, 344 A survey of pregnant women attending antenatal clinics in England reported that the time to conception following discontinuance of long-term (i.e., longer than 2 years) use of fixed-combination oral contraceptives (8.2 months) was twofold longer than time to conception following condom use (4.2 months).344
Estrogen-progestin contraceptives may decrease the quantity and quality of milk if given in the immediate postpartum period. Small amounts of the hormonal agents in estrogen-progestin contraceptives are distributed into milk and adverse effects such as jaundice and breast enlargement have been reported in nursing infants of women receiving cyclic regimens; therefore, because of the theoretical risk, some clinicians recommend that lactating women receiving high-dose postcoital contraceptive regimens use alternative milk sources for their infants for at least 24 hours after completion of the regimen.284 When possible, the use of cyclic estrogen-progestin contraceptives should be deferred until the infant has been weaned. Long-term follow-up after oral contraceptive use showed no apparent clinical effect on breast-feeding mothers or children whose mothers were breast-feeding and using oral contraceptives.285
Drugs Affecting Hepatic Microsomal Enzymes
Clinically important drug interactions may occur when estrogen-progestin oral contraceptives are administered with other drugs metabolized by the hepatic microsomal cytochrome P-450 (CYP) enzyme system.295 Metabolism of estrogens is mediated by the CYP3A4 isoenzyme, and the possibility exists that drugs that induce this isoenzyme may reduce ethinyl estradiol concentrations.295, 297
Rifampin reportedly decreases contraceptive efficacy and increases breakthrough bleeding during concomitant use with oral contraceptives. These effects have been attributed to enhanced metabolism of both the estrogenic and progestinic components of oral contraceptives, presumably by induction of hepatic microsomal enzymes. It has been suggested that similar effects may occur during concomitant therapy with other known inducers of hepatic microsomal enzymes, including barbiturates, bosentan, carbamazepine, dexamethasone, griseofulvin, phenylbutazone (no longer commercially available in the US), phenytoin, felbamate, oxcarbazepine, rifabutin, modafinil, topiramate, and primidone. Because herbal supplements containing St. John's wort ( Hypericum perforatum ) may induce hepatic cytochrome P-450 isoenzymes and the p -glycoprotein transport system, St. John's wort may decrease contraceptive efficacy of estrogen-progestin contraceptives, including that of high-dose estrogen-progestin postcoital contraceptive regimens, and increase breakthrough bleeding during concomitant use with estrogen-progestin contraceptives.308, 309, 339, 365, 366, 367, 368 Because of the risk of contraceptive failure during concomitant use of estrogen-progestin contraceptives with known inducers of hepatic microsomal enzymes, it has been suggested that alternate methods of contraception be considered in patients receiving these drugs or that oral contraceptive preparations with increased dosage be considered; however, the possibility that adverse effects may be increased with increased-dosage preparations should also be considered.
Data currently are not available concerning the effect of drugs that induce hepatic microsomal enzymes on the contraceptive efficacy of high-dose estrogen-progestin postcoital contraceptive regimens.284 However, because contraceptive failure has occurred during concomitant use of cyclic oral contraceptive regimens and known inducers of hepatic microsomal enzymes, some clinicians suggest that the dosage of postcoital estrogen-progestin contraceptive regimens may need to be increased, possibly doubled, in women receiving such inducers concomitantly.284
Estrogens are inhibitors of the CYP enzyme and may alter the pharmacokinetics of drugs metabolized by this isoenzyme.295, 297
Concomitant use of oral contraceptives and some HIV-protease inhibitors or nonnucleoside reverse transcriptase inhibitors may result in substantial changes in the area under the plasma concentration-time curve (AUC) of the estrogen and/or progestin.308, 309, 310 Concomitant use of oral contraceptives and some HIV-protease inhibitors or nonnucleoside reverse transcriptase inhibitors may reduce the efficacy of the oral contraceptive; whether this precaution applies to vaginal or transdermal estrogen-progestin contraceptives is not known.308, 309
It has been suggested that anti-infective agents which alter the GI bacterial flora may decrease the contraceptive efficacy of oral contraceptives and increase breakthrough bleeding. GI bacteria produce enzymes which hydrolyze conjugates of estrogens (e.g., ethinyl estradiol) that have been excreted into the GI tract via bile; hydrolysis of these conjugates allows enterohepatic circulation of the pharmacologically active drug. By disrupting the GI flora, anti-infective agents may decrease or eliminate enterohepatic circulation of oral contraceptives. The clinical importance of this potential interaction has not been determined; however, the manufacturers caution that concomitant use of anti-infective agents (e.g., ampicillin, chloramphenicol, neomycin, nitrofurantoin, penicillin V, sulfonamides, tetracyclines) with oral contraceptives may result in decreased efficacy of the contraceptive.
In one study in healthy women using the vaginal contraceptive ring containing ethinyl estradiol and etonogestrel (NuvaRing®), vaginal administration of a single oil-based suppository containing 1200 mg of miconazole nitrate on day 8 of the cycle increased the serum concentration of ethinyl estradiol or etonogestrel by 16 or 17%, respectively.309 While the clinical importance of these findings is unknown, the efficacy of the contraceptive vaginal ring is not expected to be affected.309 The effects of long-term administration of miconazole nitrate vaginal suppositories in women using the contraceptive vaginal ring are not known.309
Fluconazole, itraconazole and ketoconazole also may increase plasma concentrations of contraceptive steroids.309, 339, 365, 366, 367, 368
Concurrent use of oral contraceptives and troleandomycin may increase the risk of cholestatic jaundice; therefore, the drugs should be used together cautiously.
Oral contraceptives appear to decrease oxidative metabolism by the liver of some benzodiazepines (e.g., diazepam, chlordiazepoxide), while they may increase metabolism of other benzodiazepines (e.g., lorazepam, oxazepam, temazepam) that undergo glucuronide conjugation in the liver. Although the clinical importance of these potential interactions between oral contraceptives and benzodiazepines has not been determined, alterations in benzodiazepine dosage may be necessary in some patients. Although interactions have not yet been documented, other benzodiazepines that undergo oxidative metabolism in the liver include alprazolam, clorazepate, flurazepam, halazepam (no longer commercially available in the US), and prazepam.
Beta-Adrenergic Blocking Agents
Oral contraceptives have substantially increased the area under the plasma concentration-time curve (AUC) of orally administered metoprolol when the drugs were used concomitantly. It has been suggested that oral contraceptives decrease the first-pass metabolism of metoprolol. Although the clinical importance of this interaction has not been determined, women receiving oral contraceptives and metoprolol (and possibly other β-adrenergic blockers that undergo first-pass metabolism in the liver) concomitantly may require a decrease in the dosage of the β-adrenergic blocker.
Estrogens have been reported to enhance the anti-inflammatory effect of hydrocortisone in patients with chronic inflammatory skin diseases. In addition, there is limited evidence that oral contraceptives decrease the metabolic clearance of prednisolone. Increased plasma concentrations of prednisolone and other corticosteroids have been observed when these drugs were used concomitantly with oral contraceptives.339 It has been suggested that estrogens and oral contraceptives may decrease the hepatic metabolism of corticosteroids and/or alter serum corticosteroid protein binding. Patients receiving concomitant oral contraceptive-corticosteroid therapy should be observed for signs of excessive corticosteroid effects, and alterations in corticosteroid dosage may be necessary when oral contraceptives are started or discontinued.
There is limited evidence that oral contraceptives may decrease the metabolism of tricyclic antidepressants; however, the clinical importance of this effect has not been determined. Although one report indicated that oral contraceptives may inhibit the metabolism of meperidine, a subsequent study was unable to confirm this finding.
The manufacturers caution that analgesics, isoniazid, antimigraine drugs, and tranquilizers may decrease the efficacy of oral contraceptives. Oral contraceptives may alter the effects of other drugs by impairing their metabolism, altering their protein binding, or by other mechanisms. Although the clinical importance of many of these interactions has not been determined, the manufacturers caution that concomitant use of oral contraceptives with oral anticoagulants, anticonvulsants, hypotensive agents (e.g., guanethidine), vitamins, or oral antidiabetic agents may result in decreased or increased effects of these drugs. Concomitant administration of atorvastatin with an oral contraceptive increased the area under the plasma concentration-time curve (AUC) of norethindrone and ethinyl estradiol by about 30 and 20%, respectively.339, 354, 365, 366, 367, 368
Increased plasma concentrations of cyclosporine and theophylline have been observed when these drugs were used concomitantly with oral contraceptives.339 Ascorbic acid or acetaminophen may increase plasma concentrations of some synthetic estrogens.339, 354, 365, 366, 367, 368 Decreased plasma concentrations of acetaminophen and lamotrigine, and increased clearance of temazepam, salicylic acid, morphine, or clofibric acid have been observed when these drugs were administered concomitantly with oral contraceptives.308, 309, 339, 365, 366, 367, 368 The effects of oral contraceptives on plasma concentrations of lamotrigine may reduce seizure control in patients receiving concomitant therapy and dosage adjustment of lamotrigine may be necessary.365, 366, 367, 368
There is a potential for increased serum potassium concentrations in women receiving a drospirenone-containing oral contraceptive concomitantly with other drugs that increase serum potassium concentrations.365, 366, 367, 368 In one study in mildly hypertensive postmenopausal women receiving enalapril maleate (10 mg twice daily) and drospirenone in fixed combination with ethinyl estradiol (Yasmin®) or placebo, mean serum potassium concentrations (evaluated every other day for 2 weeks) relative to baseline were 0.22 mEq/L higher in those receiving drospirenone in fixed combination with ethinyl estradiol than in those receiving placebo.365, 366, 367, 368 If a drospirenone-containing oral contraceptive is used in women receiving daily, long-term therapy with agents that may increase serum potassium concentrations (e.g., angiotensin-converting enzyme (ACE) inhibitors, angiotensin II type 1 (AT1) receptor antagonists, potassium-sparing diuretics, heparin, aldosterone antagonists [spironolactone], nonsteroidal anti-inflammatory agents [NSAIAs]), the serum potassium concentration should be determined during the first oral contraceptive cycle.365, 366, 367, 368
In one study in healthy women using the vaginal contraceptive ring containing ethinyl estradiol and etonogestrel (NuvaRing®), vaginal administration of a single dose of 100 mg of water-based nonoxynol 9 spermicide gel did not affect the serum concentrations of ethinyl estradiol or etonogestrel.309 The effects of long-term vaginal administration of nonoxynol 9 spermicide gel in women using the contraceptive vaginal ring are not known.309
A decreased response to the metyrapone test may occur in women receiving oral contraceptives; however, the drugs do not interfere with the pituitary-adrenal reaction to stress. Because the adrenal responds to corticotropin, it appears that the estrogen acts on the adrenal gland to interfere with the metyrapone test. The estrogen component of oral contraceptives increases the level of circulating corticosteroid-binding globulin (transcortin) resulting in an increase in total plasma cortisol, a decrease in cortisol secretion rate, and a decrease in urinary excretion of 17-ketogenic steroids, 17-hydroxycorticosteroids, and 17-ketosteroids. Because plasma cortisol concentrations may be similar to those of patients with Cushing's syndrome and urinary steroids may suggest hypofunction, oral contraceptives should be discontinued for a few weeks before performing adrenal function tests. The dexamethasone suppression test, however, can exclude Cushing's syndrome and corticotropin tests can rule out primary adrenocortical insufficiency, even in patients receiving oral contraceptives.
Elevation in sex-hormone binding globulin (SHBG) concentration by combination estrogen-progestin contraceptives results in increased total circulating sex steroids and corticoids; however, free (unbound) concentrations of these steroids remain unchanged.299, 301 Certain other endocrine and liver function tests may also be affected by oral contraceptives. (See Cautions: Endocrine and Metabolic Effects; Hepatic Effects.)
False-positive results in the nitro blue tetrazolium (NBT) test for the diagnosis of bacterial infection have occurred in women receiving oral contraceptives.
The manufacturers state that the pathologist should be advised of oral contraceptive use when relevant specimens from an oral contraceptive user are submitted.
Acute overdosage of large doses of oral contraceptives in children reportedly produces almost no toxicity except nausea and vomiting. Withdrawal bleeding may occur in females.
Because drospirenone has antimineralocorticoid properties, serum potassium and sodium concentrations and indicators of metabolic acidosis should be monitored in the event of overdosage with a drospirenone-containing oral contraceptive.365, 366, 367, 368
The pharmacologic effects of estrogen-progestin contraceptives are complex and appear to depend on many variables including the specific drugs used, the amount and proportion of each drug, the age of the user, and the duration of administration. In general, estrogen-progestin combinations elicit, to varying degrees, many of the pharmacologic responses usually produced by endogenous estrogens and progesterone and produce numerous effects on many organs.
Estrogen-progestin combinations produce a contraceptive effect mainly by suppressing the hypothalamic-pituitary system resulting in prevention of ovulation. The estrogen acts mainly by suppressing secretion of follicle-stimulating hormone (FSH), resulting in prevention of follicular development and the rise of plasma estradiol concentration which is thought to be the stimulus for release of luteinizing hormone (LH). In combination products, the progestin appears to act mainly by inhibiting the preovulatory rise of LH. Long-term administration of these combination products results in inhibition of both FSH and LH secretion. It has been suggested that oral contraceptives may also produce a direct effect on ovarian steroidogenesis or the response of the ovary to gonadotropins. In addition, changes in the cervical mucus may prevent sperm penetration; however, further studies are required to determine the precise effects of estrogen-progestin combinations on sperm activity.
Endometrial changes depend on the type of oral contraceptive administered. Conventional-cycle combination products are usually associated with a shortened period of endometrial proliferation followed by an early but brief and limited secretory activity in the epithelium of endometrial glands. After several oral contraceptive cycles, thinning or regression of the endometrium may occur, resulting in reduced menstrual flow or possible amenorrhea.
The precise mechanism of contraceptive activity of estrogen-progestin combinations administered after intercourse (postcoital) is not known.254, 268, 285, 286, 287 However, the effect is contraceptive, not abortifacient, in nature; therefore, timing is critical to efficacy.265, 282 High-dosage estrogen-progestin combinations are only effective before pregnancy is established.345 Once implantation occurs (i.e., usually within 6-7 days after ovulation), the combinations would be ineffective in preventing pregnancy.254, 264, 275, 277, 285, 286 Estrogen-progestin combinations in high dosage provide a short, potent burst of hormonal exposure that may effectively prevent conception by delaying or inhibiting ovulation, and/or producing changes in endometrial development that are hostile to uterine implantation of the fertilized ovum, depending on when the drugs are administered relative to the menstrual cycle and the time period since intercourse.254, 258, 265, 266, 267, 268, 277, 279, 280, 282, 285, 286 Postcoital contraceptives taken before midcycle may inhibit ovulation by suppressing the midcycle surge in luteinizing hormone that is necessary for final follicular growth and ovulation.266, 268, 276, 277 Endometrial biopsies in women receiving high-dose estrogen-progestin combination contraceptives at midcycle indicate that coordinated timing of the maturation of glandular epithelium and stroma of the endometrial lining is disrupted.266, 277, 279, 282 Possible alterations in transport of the ovum through the fallopian tube, fertilization, and corpus luteum development and function have been reported with postcoital use of estrogen-progestin combinations,265, 267, 268, 285 but these effects are inconsistent and are thought to be of secondary importance as mechanisms in preventing pregnancy.258, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 282, 284, 286
Ovulation usually resumes within 3 menstrual cycles after oral contraceptives have been discontinued; however, anovulation and amenorrhea may persist for 6 months or longer in some women. After the drug is discontinued, pituitary function recovers first, followed by ovarian function; the endometrium may require up to 3 months to regain its normal histology and enzymatic activity.
Oral contraceptives may produce a wide variety of metabolic changes, possibly as a result of a direct action on the liver. The drugs may produce alterations in carbohydrate and lipid metabolism, increased serum hormone concentrations, and alterations in serum metals and plasma proteins. The estrogen appears to cause most of these metabolic effects. In one study, oral contraceptives containing mestranol and ethynodiol diacetate were shown to produce an increase in cardiac index and stroke volume, a small rise in plasma volume, and an elevation in blood pressure. Urinary tract dilatation may also occur in women receiving oral contraceptives. In nursing women, oral contraceptives may decrease the quantity and quality of milk when given immediately postpartum.
Potential noncontraceptive benefits of oral contraceptives, as evidenced from epidemiologic studies, include effects on menses, effects related to inhibition of ovulation, and effects from long-term use. Use of the drugs has been associated with improved menstrual cycle regularity and decreased incidences of blood loss, iron deficiency anemia, and dysmenorrhea. A decreased incidence of functional ovarian cysts and of ectopic pregnancies also has been associated with use of the drugs. Long-term use of oral contraceptives has been associated with a decreased incidence of formation of fibroadenomas and fibrocystic disease of the breast, a decreased incidence of some (e.g., gonococcal) pelvic inflammatory disease, and a decreased incidence of some cancers (e.g., endometrial or ovarian cancer) .
Oral contraceptive steroids are generally well absorbed from the GI tract. Following oral administration, levonorgestrel is completely absorbed. Some oral contraceptive steroids are metabolized in the GI mucosa during absorption and on first pass through the liver. Desogestrel is metabolized in the intestinal mucosa and on first pass through the liver to 3-keto-desogestrel, a metabolite believed to be responsible for the pharmacologic activity of desogestrel.233, 235 Following oral administration, the absolute bioavailability appears to be about 40% for ethinyl estradiol, 65% for norethindrone, and about 76% for desogestrel or drospirenone. Following oral administration, the relative bioavailability of desogestrel, as measured by serum concentrations of 3-keto-desogestrel (the active metabolite of desogestrel), reportedly is about 84%.235, 237 Although the absolute bioavailabilities have not been determined, about 60% of norgestimate and 60% of ethynodiol diacetate are reportedly absorbed following oral administration.
Considerable interindividual variation in peak plasma concentrations attained and extent of absorption have been reported for oral contraceptive steroids. Peak plasma concentrations of 100-200 pg/mL are reached 1-2 hours after a 50-mcg dose of ethinyl estradiol; although higher plasma concentrations have been reported, these probably represent methodologic problems. Following single-dose oral administration of ethinyl estradiol 20 mcg (in a fixed combination with levonorgestrel 0.1 mg), mean peak serum concentration was reported to be 50-62 pg/mL at approximately 1.5 hours; at steady state, mean peak ethinyl estradiol concentration of 66-77 pg/mL was reported at approximately 1.3-1.4 hours after administration.
Peak plasma norethindrone concentrations of 1.7-5 ng/mL or 5-10 ng/mL have been reported following a 0.5- or a 1-mg oral dose, respectively. The time to peak plasma norethindrone concentrations varies between 0.5-4 hours, apparently being more delayed as the dose increases.
Following oral administration of a single 0.15-mg dose of desogestrel (given in fixed combination with 30 mcg of ethinyl estradiol), average peak plasma 3-keto-desogestrel concentrations of 2.8 ng/mL are reached within 1.4 hours; at steady state (attained after 19 days or more), average peak plasma 3-keto-desogestrel concentrations of 5.8 ng/mL are reached within 1.4 hours after a dose.235, 237
Peak plasma norgestimate and 17-deacetyl norgestimate (an active metabolite of norgestimate) concentrations of 0.1 and 3.6 ng/mL are reached within 1 and 1.5 hours, respectively, following oral administration of a single 0.36-mg dose of norgestimate (given in fixed combination with 70 mcg of ethinyl estradiol); at steady state, mean plasma 17-deacetyl norgestimate concentrations of 4.4 ng/mL are reached in about 1.4 hours after a dose.234 Following single-dose oral administration of levonorgestrel 0.1 mg (in a fixed combination with ethinyl estradiol 20 mcg), mean peak serum concentration was reported to be 2.4-2.8 ng/mL at approximately 1.3-1.6 hours; at steady state, mean peak levonorgestrel concentration of 4-6 ng/mL was reported at approximately 1-1.5 hours after administration.
Plasma concentrations of desogestrel, norethindrone, and levonorgestrel at steady state are higher than predicted from single-dose kinetics because of enhanced binding of these progestins following the induction of sex hormone binding globulin (SHBG) by ethinyl estradiol.
Following single-dose oral administration of drospirenone 3 mg (in fixed combination with ethinyl estradiol 30 mcg) in women, mean peak serum concentration was reported to be 36.9 ng/mL at about 1.7 hours; at steady state, mean peak drospirenone concentrations of 78.7-87.5 ng/mL are reached in about 1.6-1.8 hours after a dose.365, 368 Although steady-state serum concentrations of drospirenone in women with mild renal impairment (creatinine clearance 50-80 mL/minute) generally are similar to those in women with normal renal function (creatinine clearance greater than or equal to 80 mL/minute), drug concentrations in women with moderate renal impairment (creatinine clearance 30-49 mL/minute) are about 37% higher than concentrations in women with normal renal function.365, 366, 367, 368
Ethinyl estradiol and etonogestrel are absorbed systemically through the mucous membrane.309, 312 Following administration of one vaginal ring delivering ethinyl estradiol 0.015 mg/24 hours and etonogestrel 0.12 mg/24 hours (NuvaRing®), peak serum concentrations of ethinyl estradiol are reached on day 2-3 and peak serum concentrations of etonogestrel are reached by day 7.312 Mean serum concentrations of ethinyl estradiol 1, 2, or 3 weeks after insertion of the ring are 19.1, 18.3, or 17.6 pg/mL, respectively and mean serum concentration of etonogestrel at these time points are 1578, 1476, or 1374 pg/mL, respectively.309 Following vaginal administration of the ring, bioavailability appears to be about 56% for ethinyl estradiol and 100% for etonogestrel.309, 312
Ethinyl estradiol and norelgestromin are also absorbed systemically through the skin.308, 314, 315, 316 Following topical application of one system containing ethinyl estradiol 0.75 mg and norelgestromin 6 mg (Ortho Evra®), peak serum concentrations of ethinyl estradiol and norelgestromin are reached within 48 hours and are maintained at approximately steady state throughout the application period (7 days).308 In clinical studies, steady state serum concentrations of ethinyl estradiol and norelgestromin were reached during the second week of patch wear; mean steady-state serum concentrations of ethinyl estradiol ranged from 11.2-137 pg/mL and steady-state concentrations of norelgestromin ranged from 0.305-1.53 pg/mL.308 Serum concentrations generally are consistent from all studies and application sites (i.e., abdomen, buttock, upper outer arm, upper torso).308, 314, 315, 316 Results of multi-dose studies indicate that steady-state area under the plasma-concentration time curve (AUC) of ethinyl estradiol and norelgestromin may increase slightly over time compared with values from week 1 of cycle 1.308 Following 3 consecutive cycles of patch wear, mean steady-state serum concentrations of ethinyl estradiol were 49.6 pg/mL (coefficient of variation of 54.4%) and steady-state concentrations of norelgestromin were 0.7 ng/mL (coefficient of variation of 45.3%) at week 3.308 Health club activities (i.e., sauna, whirlpool, treadmill) or a cold water bath do not result in clinically important changes in the absorption of ethinyl estradiol or norelgestromin compared with normal wear.308, 316
The pharmacokinetic profile for the transdermal contraceptive system containing ethinyl estradiol and norelgestromin (Ortho Evra®) differs from the profile for oral contraceptive preparations.308 Overall exposure to ethinyl estradiol and norelgestromin is higher in women receiving Ortho Evra® than in women receiving an oral contraceptive preparation containing ethinyl estradiol 35 mcg and norgestimate 0.25 mg.308 The average plasma concentration and AUC (from 0-168 hours) of ethinyl estradiol at steady-state in women receiving Ortho Evra® are 55-60% higher and peak plasma concentrations are 25% lower than values in women receiving an oral contraceptive preparation containing ethinyl estradiol 35 mcg (average weekly exposure [AUC 0-168] to the oral contraceptive calculated as 7 times the AUC from 0-24 hours).308
Contraceptive steroids are widely distributed into body tissues and fluids. The apparent volume of distribution for contraceptive steroids reportedly ranges from 1.5-4.3 L/kg.
Contraceptive steroids are extensively bound to plasma proteins. Ethinyl estradiol is about 98% protein bound, mainly to albumin. Norethindrone is highly (greater than 95%) protein bound to albumin and sex hormone binding globulin (SHBG). Levonorgestrel and 3-keto-desogestrel (the active metabolite of desogestrel) are 93-98 and 96% protein bound, respectively; levonorgestrel is about 34-50 or 48-65% bound to albumin or SHBG, respectively, while 3-keto-desogestrel is about 64 or 32% bound to albumin or SHBG, respectively.238 Drospirenone is about 97% protein bound, presumably to albumin.305, 365, 366, 367, 368 Etonogestrel is about 32% bound to SHBG and 66% bound to albumin.309 Norelgestromin is reportedly more than 97% bound to serum proteins (mainly albumin).308 Norgestimate, norelgestromin, drospirenone, and ethinyl estradiol do not appear to bind to SHBG.234, 295, 238, 305, 365, 366, 367, 368 The binding capacity of SHBG for progestins is enhanced by ethinyl estradiol and by other enzyme-inducing drugs such as carbamazepine, phenobarbital, or rifampin. The binding of progestins to albumin and SHBG is low affinity, high capacity and high affinity, low capacity, respectively. Only the unbound fraction of contraceptive steroids is biologically active.
Contraceptive steroids may be distributed into bile. Small amounts of oral contraceptive steroids are also distributed into milk. The plasma-to-milk ratios of levonorgestrel and norethindrone concentrations are reportedly 100:15-100:25 and 100:10, respectively. It has been estimated that about 0.02% of a 50-mcg dose of ethinyl estradiol is distributed into milk.
The elimination half-life has been reported to be 11-45 hours for levonorgestrel, about 28 hours for norelgestromin, about 30 hours for drospirenone or etonogestrel, 5-14 hours for norethindrone, 6-45 hours for ethinyl estradiol, and 12-58 hours for 3-keto-desogestrel (the active metabolite of desogestrel).232, 233, 235, 237, 238, 285, 295, 308, 309, 365, 366, 367, 368 Serum concentrations of norethindrone return to near baseline levels 24 hours after a single 0.35-mg dose, making rigid adherence to once-daily administration necessary for efficacy.300 Plasma clearance of norethindrone and ethinyl estradiol each is about 0.4 L/hour per kg.299 Serum concentrations of norgestimate generally are below the lower detection limits of assay within 5 hours of single or multiple oral dosing,234, 236 and determination of half-life of the drug may not be accurate.234 An elimination half-life of 12-30 hours has been reported for 17-acetyl norgestimate (an active metabolite of norgestimate).236 Following removal of the transdermal preparation containing ethinyl estradiol 0.75 mg and norelgestromin 6 mg (Ortho Evra®), serum concentrations of ethinyl estradiol and norelgestromin decline to low or undetectable concentrations within 3 days.308
Oral contraceptive steroids are metabolized mainly in the liver and/or GI mucosa during absorption. Ethinyl estradiol and norethindrone appear to undergo extensive first-pass metabolism. Levonorgestrel does not appear to undergo first-pass metabolism.295, 296
Ethinyl estradiol is mainly metabolized via aromatic hydroxylation by hepatic microsomal isoenzyme cytochrome P-450 (CYP) 3A4. The major hydroxylated metabolite of ethinyl estradiol is 2-hydroxy-ethinylestradiol, which is thought to contribute to some of the adverse cardiovascular effects of the drug. The hydroxylated metabolite is further metabolized by methylation and glucuronidation prior to urinary and fecal excretion. Ethinyl estradiol and its metabolites undergo glucuronide and sulfate conjugation. The major first-pass metabolite of ethinyl estradiol is its sulfate conjugate. Ethinyl estradiol undergoes extensive enterohepatic circulation as glucuronide and sulfate conjugates. Bacteria in the GI tract hydrolyze these conjugates (excreted into the GI tract via bile), allowing reabsorption of ethinyl estradiol. Mestranol is rapidly metabolized mainly to ethinyl estradiol by demethylation; ethinyl estradiol is thought to be principally responsible for the estrogenic effects of mestranol. Following oral administration of a single 50- or 100-mcg dose of mestranol, the ratio of plasma mestranol to ethinyl estradiol concentrations is reportedly 0.24:1; in the usual oral dosages, mestranol and ethinyl estradiol are considered approximately equipotent.
Levonorgestrel and norethindrone are metabolized mainly by reduction, hydroxylation or oxidation, and glucuronide and sulfate conjugation.295, 296, 299 Unlike ethinyl estradiol, levonorgestrel and norethindrone do not undergo appreciable enterohepatic circulation; norethindrone is partially excreted, mainly as metabolites, in the feces via biliary elimination. Levonorgestrel and its metabolites are principally (40-68%) excreted in the urine.285, 295, 296 Desogestrel is rapidly and completely metabolized by hydroxylation in the intestinal mucosa and on first pass through the liver to 3-keto-desogestrel, a metabolite believed to be responsible for the pharmacologic actions of desogestrel; metabolites with no pharmacologic actions also have been identified and these metabolites may undergo glucuronide and sulfate conjugation.233, 235 Norgestimate is metabolized extensively, mainly by hydrolysis, reduction, and hydroxylation to 17-deacetyl norgestimate, 3-keto-norgestimate, and levonorgestrel, metabolites that subsequently may undergo glucuronide and sulfate conjugation; however, it is believed that only 17-deactyl norgestimate contributes to the pharmacologic activity of norgestimate.234 Limited information is available on the pharmacokinetics of norethindrone acetate and ethynodiol diacetate; however, the drugs reportedly are rapidly metabolized to norethindrone. Drospirenone is metabolized to 2 major inactive metabolites, which according to one study are formed independently of the cytochrome P-450 enzyme system. 305, 365, 366, 367, 368 The manufacturers state that drospirenone is metabolized only to a minor extent in vitro, mainly by CYP3A4.365, 366, 367, 368 At least 20 metabolites have been detected in urine or feces.365, 366, 367, 368
Contraceptive steroids are excreted in urine and feces, principally as glucuronide and sulfate conjugates of the drugs and metabolites. Unchanged drug and unconjugated metabolites may also be excreted to some extent in urine and feces; although this may be particularly true for ethinyl estradiol, the metabolism and excretion of this and other oral contraceptive steroids is complex and variable, and specialized references should be consulted for more detailed information.
Estrogen-progestin combination contraceptives contain estrogenic and progestinic steroids and are commercially available as oral tablets, an intravaginal ring, and a transdermal system.
The estrogenic component of commercially available oral contraceptive combinations is ethinyl estradiol or mestranol; the estrogenic component of vaginal and transdermal contraceptive combinations is ethinyl estradiol.
Ethinyl estradiol is a semisynthetic steroidal estrogen; the compound is the most orally active estrogenic drug currently available. The estrogenic potency of ethinyl estradiol is about 20 times that of diethylstilbestrol (no longer commercially available in the US). Mestranol, the 3-methyl ester of ethinyl estradiol, is slightly less active than ethinyl estradiol.
The progestinic component of commercially available oral contraceptive combinations is desogestrel, drospirenone, ethynodiol diacetate, levonorgestrel, norethindrone, norethindrone acetate, norgestimate, or norgestrel. These progestins are mainly derivatives of 19-nortestosterone; ethynodiol diacetate is a 17α-hydroxyprogesterone derivative, and drospirenone is structurally related to spironolactone. Norgestrel is a racemic mixture; levonorgestrel is the pharmacologically active isomer. In terms of oral progestational activity, desogestrel, levonorgestrel, and norgestrel are the most potent of these progestins and norethindrone is the least potent. Levonorgestrel and norgestrel have the greatest androgenic activity while norgestimate and norethindrone have the weakest androgenic activity. Desogestrel, etonogestrel, and norgestimate appear to have a substantially higher selectivity index (ratio of affinity for progesterone receptors versus affinity for androgen receptors) than conventional progestins (e.g., levonorgestrel, norethindrone).232, 243 Drospirenone has progestational, antimineralocorticoid, and antiandrogenic activity.303, 304, 305, 365, 366, 367, 368
The progestinic component of the commercially available transdermal system (Ortho Evra®) or contraceptive vaginal ring (NuvaRing®) is norelgestromin (the active metabolite of orally administered norgestimate) or etonogestrel (the active metabolite of desogestrel), respectively.308, 309
Intravaginal ethinyl estradiol in fixed combination with etonogestrel (NuvaRing®) is commercially available as a non-biodegradable, flexible ring that also contains magnesium stearate and ethylene vinyl acetate copolymers.309
Transdermal ethinyl estradiol in fixed combination with norelgestromin (Ortho Evra®) is commercially available as a system that consists of an outer layer of polyethylene/polyester film and a drug reservoir consisting of ethinyl estradiol and norelgestromin in a polyisobutylene/polybutene adhesive matrix; a polyethylene terephthalate film is attached to the adhesive surface and should be removed prior to application.308
Estrogen-progestin combinations generally should be stored at room temperature in a well-closed container, unless otherwise specified by the manufacturer. Commercially available oral contraceptives are provided in mnemonic (memory-aid) dispensing packages which are exempted from the child-safety packaging requirements of the US Poison Prevention Packaging Act of 1970. Vaginal ethinyl estradiol in fixed combination with etonogestrel (Nuva Ring®) should be refrigerated at 2-8°C until dispensed.309 Once dispensed, the vaginal ring can be stored for up to 4 months at 25°C, but may be exposed to temperatures ranging from 15-30°C.309 Transdermal ethinyl estradiol in fixed combination with norelgestromin (Ortho Evra®) should be stored at 25°C, but may be exposed to temperatures ranging from 15-30°C.308 After removal from the protective pouch, the transdermal system should be applied immediately.308
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, monophasic regimen | 20 mcg with Drospirenone 3 mg* | Beyaz® (24 tablets with levomefolate calcium 0.451 mg plus 4 tablets containing only levomefolate calcium 0.451 mg) | |
Yaz® (24 tablets plus 4 inert tablets) | Bayer HealthCare | |||
20 mcg with Levonorgestrel 0.09 mg | Lybrel® (28 tablets) | |||
20 mcg with Levonorgestrel 0.1 mg | Alesse®-21 (21 tablets) | Wyeth | ||
Alesse®-28 (21 tablets plus 7 inert tablets) | Wyeth | |||
Aviane® 28 ( 21 tablets plus 7 inert tablets) | ||||
Lessina® 28 (21 tablets plus 7 inert tablets) | Barr | |||
Levlite® 28 (21 tablets plus 7 inert tablets) | ||||
LoSeasonique® (84 tablets plus 7 tablets containing ethinyl estradiol 10 mcg) | ||||
20 mcg with Norethindrone Acetate 1 mg | Loestrin® 21 1/20 (21 tablets) | |||
Loestrin® Fe 1/20 (21 tablets plus 7 tablets containing only ferrous fumarate 75 mg) | Pfizer | |||
Loestrin® 24 Fe (24 tablets plus 4 tablets containing only ferrous fumarate 75 mg) | ||||
Microgestin® Fe 1/20 (21 tablets plus 7 tablets containing only ferrous fumarate 75 mg) | ||||
30 mcg with Desogestrel 0.15 mg | Apri® 28 (21 tablets plus 7 inert tablets) | Barr | ||
Desogen® (21 tablets plus 7 inert tablets) | ||||
Ortho-Cept® 28 (21 tablets plus 7 inert tablets) | ||||
30 mcg with Drospirenone 3 mg* | Safyral® (21 tablets with levomefolate calcium 0.451 mg plus 7 tablets containing only levomefolate calcium 0.451 mg) | Bayer HealthCare | ||
Yasmin® (21 tablets plus 7 inert tablets) | Bayer HealthCare | |||
30 mcg with Levonorgestrel 0.15 mg | Levlen® 21 (21 tablets) | Berlex | ||
Levlen® 28 (21 tablets plus 7 inert tablets) | Berlex | |||
Levora® 0.15/30-28 (21 tablets plus 7 inert tablets) | Watson | |||
Nordette®-28 (21 tablets plus 7 inert tablets) | ||||
Portia® 28 (21 tablets plus 7 inert tablets) | Barr | |||
Seasonale® (84 tablets plus 7 inert tablets) | Duramed | |||
Seasonique® (84 tablets plus 7 tablets containing ethinyl estradiol 10 mcg) | Duramed | |||
30 mcg with Norethindrone Acetate 1.5 mg | Loestrin® 21 1.5/30 (21 tablets) | Pfizer | ||
Loestrin® Fe 1.5/30 (21 tablets plus 7 tablets containing only ferrous fumarate 75 mg) | Pfizer | |||
Microgestin® Fe 1.5/30 (21 tablets plus 7 tablets containing only ferrous fumarate 75 mg) | Watson | |||
30 mcg with Norgestrel 0.3 mg | Cryselle® (21 tablets plus 7 inert tablets) | Barr | ||
Lo/Ovral® (21 tablets) | Wyeth | |||
Lo/Ovral®-28 (21 tablets plus 7 inert tablets) | Wyeth | |||
Low-Ogestrel® 28 (21 tablets plus 7 inert tablets) | Watson | |||
35 mcg with Ethynodiol Diacetate 1 mg | Demulen 1/35®-21 (21 tablets) | Pfizer | ||
Demulen 1/35®-28 (21 tablets plus 7 inert tablets) | Pfizer | |||
Zovia® 1/35E-28 (21 tablets plus 7 inert tablets) | Watson | |||
35 mcg with Norethindrone 0.4 mg | Ovcon®/35. 21-Day (21 tablets) | Warner Chilcott | ||
Ovcon®/35 28-Day (21 tablets plus 7 inert tablets) | Warner Chilcott | |||
35 mcg with Norethindrone 0.5 mg | Brevicon® 28-Day (21 tablets plus 7 inert tablets) | Watson | ||
Modicon® 28 (21 tablets plus 7 inert tablets) | Janssen | |||
Necon®-0.5/35-21 (21 tablets) | Watson | |||
Necon®-0.5/35-28 (21 tablets plus 7 inert tablets) | Watson | |||
Nelova® 0.5/35E 28 (21 tablets plus 7 inert tablets) | Warner Chilcott | |||
Nortrel® 0.5/35 28 (21 tablets plus 7 inert tablets) | Barr | |||
35 mcg with Norethindrone 1 mg | Necon®-1/35 28 (21 tablets plus 7 inert tablets) | Watson | ||
Norinyl® 1+35 28-Day (21 tablets plus 7 inert tablets) | Watson | |||
Nortrel® 1/35 21 (21 tablets) | Barr | |||
Nortrel® 1/35 28 (21 tablets plus 7 inert tablets) | Barr | |||
Ortho-Novum® 1/35 28 (21 tablets plus 7 inert tablets) | Janssen | |||
35 mcg with Norgestimate 0.25 mg | MonoNessa® (21 tablets plus 7 inert tablets) | Watson | ||
Ortho-Cyclen® 28 (21 tablets plus 7 inert tablets) | Janssen | |||
Sprintec® (21 tablets plus 7 inert tablets) | Barr | |||
50 mcg with Ethynodiol Diacetate 1 mg | Demulen 1/50®-21 (21 tablets) | Pfizer | ||
Demulen 1/50®-28 (21 tablets plus 7 inert tablets) | Pfizer | |||
Zovia® 1/50E-28 (21 tablets plus 7 inert tablets) | Watson | |||
50 mcg with Norethindrone 1 mg | Ovcon®/50 28-Day (21 tablets plus 7 inert tablets) | Warner Chilcott | ||
50 mcg with Norgestrel 0.5 mg | Ogestrel® 0.5/50-28 (21 tablets plus 7 inert tablets) | Watson | ||
Ovral® (21 tablets) | Wyeth | |||
Ovral®-28 (21 tablets plus 7 inert tablets) | Wyeth | |||
20 mcg with Desogestrel 0.15 mg (21 tablets), and 10 mcg (5 tablets), | Kariva® (26 tablets plus 2 inert tablets) | Barr | ||
Mircette® (26 tablets plus 2 inert tablets) | Organon | |||
Tablets, chewable | 35 mcg with Norethindrone 0.4 mg | Ovcon® 35 Fe (21 tablets plus 7 tablets containing only ferrous fumarate 75 mg) | Warner Chilcott | |
Femcon® Fe (21 tablets plus 7 tablets containing only ferrous fumarate 75 mg) | Warner Chilcott | |||
Tablets, biphasic regimen | 35 mcg with Norethindrone 0.5 mg (10 tablets) and 35 mcg with Norethindrone 1 mg (11 tablets) | Necon® 10/11-21 (21 tablets) | Watson | |
Necon® 10/11-28 (21 tablets plus 7 inert tablets) | Watson | |||
Tablets, triphasic regimen | 20 mcg with Norethindrone Acetate 1 mg (5 tablets), 30 mcg with Norethindrone Acetate 1 mg (7 tablets), and 35 mcg with Norethindrone Acetate 1 mg (9 tablets) | Estrostep® 21 (21 tablets) | Pfizer | |
Estrostep® Fe (21 tablets plus 7 tablets containing only ferrous fumarate 75 mg) | Pfizer | |||
25 mcg with Desogestrel 0.1 mg (7 tablets), 25 mcg with Desogestrel 0.125 mg (7 tablets), and 25 mcg with Desogestrel 0.150 mg (7 tablets) | Cyclessa® (21 tablets plus 7 inert tablets) | Organon | ||
25 mcg with Norgestimate 0.18 mg (7 tablets), 25 mcg with Norgestimate 0.215 mg (7 tablets), and 25 mcg with Norgestimate 0.25 mg (7 tablets) | Ortho Tri-Cyclen® Lo (21 tablets plus 7 inert tablets) | Janssen | ||
30 mcg with Levonorgestrel 0.05 mg (6 tablets), 40 mcg with Levonorgestrel 0.075 mg (5 tablets), and 30 mcg with Levonorgestrel 0.125 mg (10 tablets) | Enpresse® 28 (21 tablets plus 7 inert tablets) | Barr | ||
Tri-Levlen® 21 (21 tablets) | Berlex | |||
Tri-Levlen® 28 (21 tablets plus 7 inert tablets) | Berlex | |||
Triphasil®-21 (21 tablets) | Wyeth | |||
Triphasil®-28 (21 tablets plus 7 inert tablets) | Wyeth | |||
Trivora®-28 (21 tablets plus 7 inert tablets) | Watson | |||
35 mcg with Norethindrone 0.5 mg (7 tablets), 35 mcg with Norethindrone 0.75 mg (7 tablets), and 35 mcg with Norethindrone 1 mg (7 tablets) | Necon® 7/7/7 (21 tablets plus 7 inert tablets) | Watson | ||
Ortho-Novum® 7/7/7 28 (21 tablets plus 7 inert tablets) | Janssen | |||
35 mcg with Norethindrone 0.5 mg (7 tablets), 35 mcg with Norethindrone 1 mg (9 tablets), and 35 mcg with Norethindrone 0.5 mg (5 tablets) | Tri-Norinyl®-28 (21 tablets plus 7 inert tablets) | Watson | ||
35 mcg with Norgestimate 0.18 mg (7 tablets), 35 mcg with Norgestimate 0.215 mg (7 tablets), and 35 mcg with Norgestimate 0.25 mg (7 tablets) | Ortho Tri-Cyclen® 28 (21 tablets plus 7 inert tablets) | Janssen | ||
Tri-Sprintec® (21 tablets plus 7 inert tablets) | Barr | |||
Topical | Transdermal System | 0.75 mg with 6 mg Norelgestromin/20 cm2 | Janssen | |
Vaginal | Ring | 0.015 mg with 0.12 mg Etonogestrel/24 hours (2.7 mg with 11.7 mg Etonogestrel/ring | Organon |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, monophasic regimen | 50 mcg with Norethindrone 1 mg | Necon® 1/50-21 (21 tablets) | Watson |
Necon® 1/50-28 (21 tablets plus 7 inert tablets) | Watson | |||
Norinyl® 1+50 28-Day (21 tablets plus 7 inert tablets) | Watson | |||
Ortho-Novum® 1/50 28 (21 tablets plus 7 inert tablets) | Janssen |
201. Pinto MR. Possible effects of hormonal contraceptives on human mitotic chromosomes. Mutat Res . 1986; 169:149-57. [PubMed 3951467]
202. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. Oral-contraceptive use and the risk of breast cancer. N Engl J Med . 1986; 315:405-11. [PubMed 3736618]
203. Shapiro S. Oral contraceptives—time to take stock. N Engl J Med . 1986; 315:450-1. [PubMed 3736622]
204. Lipnick RJ, Buring JE, Hennekens CH et al. Oral contraceptives and breast cancer: a prospective cohort study. JAMA . 1986; 255:58-61. [PubMed 3940306]
205. Sattin RW, Wingo PA, Lee NC. Oral-contraceptive use and the risk of breast cancer. N Engl J Med . 1987; 316:163-4.
220. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. Combination oral contraceptive use and the risk of endometrial cancer: the Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. JAMA . 1987; 257:796-800. [PubMed 3027423]
221. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. The reduction in risk of ovarian cancer associated with oral-contraceptive use: the Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. N Engl J Med . 1987; 316:650-5. [PubMed 3821795]
222. Anon. Manufacturers phase out high-dose oral contraceptives. FDA Drug Bull . 1988; 18:19.
223. Miller DR, Rosenberg L, Kaufman DW et al. Breast cancer before age 45 and oral contraceptive use: new findings. Am J Epidemiol . 1989; 129:269-80. [PubMed 2912040]
224. Stadel BV, Lai SH, Schlesselman JJ et al. Oral contraceptives and premenopausal breast cancer in nulliparous women. Contraception . 1988; 38:287-99. [PubMed 3168449]
225. Pike MC, Henderson BE, Krailo MD et al. Breast cancer in young women and use of oral contraceptives: possible modifying effect of formulation and age at use. Lancet . 1983; 2:926-30. [PubMed 6138501]
226. Centers for Disease Control. Oral contraceptive use and the risk of breast cancer in young women. MMWR Morb Mortal Wkly Rep . 1984; 33:353-4. [PubMed 6427584]
227. Anon. Oral contraceptives and cancer. FDA Drug Bull . 1984; 14:2-3. [PubMed 6734989]
228. McPherson K, Neil A, Vessey MP et al. Oral contraceptives and breast cancer. Lancet . 1983; 2:1414-5. [PubMed 6140506]
229. Meirik O, Lund E, Adami HO et al. Oral contraceptive use and breast cancer in young women: a joint national case-control study in Sweden and Norway. Lancet . 1986; 2:650-4. [PubMed 2876135]
230. Food and Drug Administration Fertility and Maternal Health Drugs Advisory Committee. Summary minutes. 1989 Jan 5-6.
231. Irwin KL, Rosero-Bixby L, Oberle MW et al. Oral contraceptives and cervical cancer risk in Costa Rica: detection bias or causal association? JAMA . 1988; 259:59-64.
232. Kaplan B. Desogestrel, norgestimate, and gestodene: the newer progestins. Ann Pharmacother . 1995; 29:736-42. [PubMed 8520092]
233. McClamrock HD, Adashi EY. Pharmacokinetics of desogestrel. Am J Obstet Gynecol . 1993; 168:1021-8. [PubMed 8447355]
234. McGuire JL, Phillips A, Hahn DW. Pharmacologic and pharmacokinetic characteristics of norgestimate and its metabolites. Am J Obstet Gynecol . 1990; 163:2127-31. [PubMed 2124088]
235. Ortho Pharmaceutical Corporation. Ortho-Cept™ (desogestrel and ethinyl estradiol) tablets prescribing information (dated 1993 May). In: Physicians' desk reference. 49th ed. Montvale NJ: Medical Economics Company Inc; 1995:1781-2.
236. Ortho Pharmaceutical Corporation. Ortho-Cyclen® and Ortho Tri-Cyclen® (norgestimate/ethinyl estradiol) tablets prescribing information (dated 1993 Jul). In: Physicians' desk reference. 49th ed. Montvale, NJ: Medical Economics Company Inc; 1995:1788-9.
237. Organon Inc. Desogen® (desogestrel and ethinyl estradiol) tablets prescribing information (dated 1993 Apr 1). In: Physicians' desk reference. 49th ed. Montvale, NJ: Medical Economics Company Inc; 1995:1744-51.
238. Fotherby K, Caldwell ADS. New progestogens in oral contraception. Contraception . 1994; 49:1-32. [PubMed 8137623]
239. Anon. Oral contraceptives and risk of blood clots. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 1995 Nov 14.
240. Guillebaud J. Advising women on which pill to take: the informed user should be the chooser. BMJ . 1995; 311:1112. [PubMed 7580698]
241. MacRae K, Kay C. Third generation oral contraceptive pills: is the scare over the increased risk of thrombosis justified? Br Med J . 1995; 311:1112. Editorial.
242. Carnall D. Controversy rages over new contraceptive data. BMJ . 1995; 311:1117-8.
243. Burkman RT. Lipid metabolism effects with desogestrel-containing oral contraceptives. Am J Obstet Gynecol . 1993; 168:1033-40. [PubMed 8447357]
244. Lippman J. Long-term profile of a new progestin. Int J Fertil . 1992; 37(Suppl 4):218-22. [PubMed 1362189]
245. Burkman RT Jr, Kafrissen ME, Olson W et al. Lipid and carbohydrate effects of a new triphasic oral contraceptive containing norgestimate. Acta Obstet Gynecol Scand Suppl . 1992; 156:5-8. [PubMed 1324556]
246. Dawood MY. Considerations in selecting appropriate medical therapy for endometriosis. Int J Gynaecol Obstet . 1993; 40(Suppl):S29-42. [PubMed 8099023]
247. Dawood MY. Hormonal therapies for endometriosis: implications for bone metabolism. Acta Obstet Gynecol Scand Suppl . 1994; 159:22-34. [PubMed 8209669]
248. Wathen PI, Henderson MC, Witz CA. Abnormal uterine bleeding. Med Clin North Am . 1995; 79:329-44. [PubMed 7877394]
249. Shaw RW. Assessment of medical treatments for menorrhagia. Br J Obstet Gynaecol . 1994; 101(Suppl 11):15-8. [PubMed 8043556]
250. Drugs used in gynecologic disorders. In: Drug evaluations subscription. Chicago, IL: American Medical Association; II/:6:1-18, Spring 1991.
251. Anon. Choice of contraceptives. Med Lett Drugs Ther . 1995; 37:9-12. [PubMed 7823877]
252. Fotherby K, Caldwell AD. New progestogens in oral contraception. Contraception . 1994; 49:1-32. [PubMed 8137623]
253. Berer M, Coutinho E, Delano G et al. Consensus statement on emergency contraception. Contraception . 1995; 52:211-3. [PubMed 8605777]
254. Anon. Ovral as a “morning-after” contraceptive. Med Lett Drugs Ther . 1989; 31:93-4. [PubMed 2796842]
255. Zuliani G, Colombo UF, Molla R. Hormonal postcoital contraception with an ethinylestradiol-norgestrel combination and two danazol regimens. Eur J Obstet Gynecol Reprod Biol . 1990; 37:253-60. [PubMed 2227068]
256. Silvestre L, Bouali Y, Ulmann A. Postcoital contraception: myth or reality? Lancet . 1991; 338:39-41.
257. Trussell J, Ellertson C, Stewart F. The effectiveness of the Yuzpe regimen of emergency contraception. Fam Plan Perspect . 1996; 28:58-64,87.
258. Van Santen MR, Haspels AA. A comparison of high-dose estrogens versus low-dose ethinylestradiol and norgestrel combination in postcoital interception: a study in 493 women. Fertil Steril . 1985; 43:206-13. [PubMed 3881294]
259. Glasier A, Thong KJ, Dewar M et al. Mifepristone (RU 486) compared with high-dose estrogen and progestogen for emergency postcoital contraception. N Engl J Med . 1992; 327:1041-4. [PubMed 1522839]
260. Webb AMC, Russell J, Elstein M. Comparison of Yuzpe regimen, danazol, and mifepristone (RU486) in oral postcoital contraception. BMJ . 1992; 305:927-31. [PubMed 1458074]
261. Bagshaw SN, Edwards D, Tucker AK. Ethinyl oestradiol and D-norgestrel is an effective emergency postcoital contraceptive: a report of its use in 1,200 patients in a family planning clinic. Aust N Zealand J Obstet Gynaecol . 1988; 28:137-40.
262. American College of Obstetricians and Gynecologists. ACOG technical bulletin: hormonal contraception. Int J Gynaecol Obstet . 1995; 48:115-26. [PubMed 7698374]
263. Fasoli M, Parazzini F, Cecchetti G et al. Post-coital contraception: an overview of published studies. Contraception . 1989; 39:459-68. [PubMed 2656085]
264. Barnett AA. FDA committee finds “morning after” use of oral contraceptives safe: but drug companies will not seek FDA approval for emergency indication. Pharm Today . 1996; 2:3,14.
265. Food and Drug Administration. Prescription drug products; certain combined oral contraceptives for use as postcoital emergency contraception. Notice. [Docket No. 96N-0492] Fed Regist . 1997; 62:8610-2.
266. Ling WY, Robichaud A, Zayid I et al. Mode of action of dl-norgestrel and ethinylestradiol combination in postcoital contraception. Fertil Steril . 1979; 32:297-302. [PubMed 488410]
267. Hall DJ, Murdoch LAL, Lisowski FH et al. Postcoital contraception. Hosp Pharm . 1985; 20:153-4, 156.
268. Williams CL, Stancel GM. Estrogens and progestins. In: Hardman JG, Limbird LE, Molinoff PB et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill; 1995:1411-40.
269. Food and Drug Administration. Diethylstilbestrol as postcoital oral contraceptive; patient labeling. [Docket No. 75-3201] Fed Regist . 1975; 40:5351-5.
270. Harlap S, Eldor J. Births following oral contraceptive failures. Obstet Gynecol . 1980; 55:447-52. [PubMed 7366901]
271. Savolainen E, Saksela E, Saxen L. Teratogenic hazards of oral contraceptives analyzed in a national malformation register. Am J Obstet Gynecol . 1981; 140:521-4. [PubMed 7246686]
272. Janerich DT, Piper JM, Glebatis DM. Oral contraceptives and birth defects. Am J Epidemiol . 1980; 112:73-9. [PubMed 7395856]
273. Ferencz C, Matanoski GM, Wilson PD et al. Maternal hormone therapy and congenital heart disease. Teratology . 1980; 21:225-39. [PubMed 7394725]
274. Rothman KJ, Fyler DC, Goldblatt A et al. Exogenous hormones and other drug exposures of children with congenital heart disease. Am J Epidemiol . 1979; 109:433-9. [PubMed 443241]
275. Trussell J, Ellertson C, Rodriguez G. The Yupze regimen of emergency contraception: how long after the morning after? Obst Gynecol . 1996; 88:152-4.
276. Swahn ML, Westerlund P, Johannisson E et al. Effect of post-coital contraceptive methods on the endometrium and the menstrual cycle. Acta Obstet Gynecol Scand . 1996; 75:738-44. [PubMed 8906009]
277. Grou F, Rodrigues I. The morning after pill—how long after? Am J Obstet Gynecol . 1994; 171:1529-34.
278. Reviewers' comments (personal observations).
279. Ling WY, Wrixon W, Acorn T et al. Mode of action of dl-norgestrel and ethinylestradiol combination in postcoital contraception. III. Effect of preovulatory administration following the luteinizing hormone surge on ovarian steroidogenesis. Fertil Steril . 1983; 40:631-6. [PubMed 6628707]
280. Ling WY, Wrixon W, Zayrid I et al. Mode of action of dl-norgestrel and ethinylestradiol combination in postcoital contraception. II. Effect of postovulatory administration of ovarian function and endometrium. Fertil Steril . 1983; 39:292-7. [PubMed 6402387]
281. Trussell J, Stewart F, Guest F et al. Emergency contraceptive pills: a simple proposal to reduce unintended pregnancies. Fam Plan Perspect . 1992; 24:269-73.
282. Anon. Emergency oral contraception. ACOT Pract Patt . 1996; 3:6-8.
283. Bracken MB. Oral contraception and congenital malformations in offspring: a review and meta-analysis of the prospective studes. Obstet Gynecol . 1990; 76:552-7. [PubMed 2143279]
284. World Health Organization Program for Appropriate Technology in Health (PATH). Emergency contraception: a resource manual for providers. Seattle, WA; 1997 Mar 3.
285. Gynétics Incorporated. Preven® Emergency Contraceptive Kit prescribing information. Somerville, NJ; 1998 Sept.
286. Glasier A. Emergency postcoital contraception. N Engl J Med . 1997; 337:1058-64. [PubMed 9321535]
287. Task Force on Postovulatory Methods of Fertility Regulation. Randomized controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. Lancet . 1998; 352:428-33. [PubMed 9708750]
288. Ho PC, Kwan MSW. A prospective randomized comparison of levonorgestrel with the Yuzpe regimen in post-coital contraception. Hum Reprod . 1993; 8:389-92. [PubMed 8473453]
289. Ellertson C. History and efficacy of emergency contraception: beyond Coca-Cola. Fam Plann Perspect . 1996; 28:44-8. [PubMed 8777937]
290. Centers for Disease Control and Prevention. 1998 guidelines for treatment of sexually transmitted diseases. MMWR Morb Mortal Wkly Rep . 1998; 47(No. RR-1):1-116. [PubMed 9450721]
291. Gynetics Inc. Preven® (levonorgestrel and ethinyl estradiol tablets and pregnancy test) Emergency Contraceptive Kit detailed patient information. Somerville, NJ; 1998 Sep.
292. Grabrick DM, Hartmann LC, Cerhan JR et al. Risk of breast cancer with oral contraceptive use in women with a family history of breast cancer. JAMA . 2000; 284:1791-8. [PubMed 11025831]
293. Burke W. Oral contraceptives and breast cancer: a note of caution for high-risk women. JAMA . 2000; 284:1837-8. [PubMed 11025837]
294. Rowan JP. ''Estrophasic'' dosing: a new concept in oral contraceptive therapy. Am J Obstet Gynecol . 1999; 180:S302-6. [PubMed 9988834]
295. Berlex Laboratories. Levlite®, Tri-Levlen®, and Levlen® (levonorgestrel and ethinyl estradiol) tablets prescribing information (dated Oct 1998). In: Physicians' desk reference. 55th ed. Montvale NJ: Medical Economics Company Inc; 2001:916-24.
296. Wyeth-Ayerst. Alesse® (levonorgestrel and ethinyl estradiol) tablets prescribing information. In: Physicians' desk reference. 55th ed. Montvale NJ: Medical Economics Company Inc; 2001:3337-42.
297. Michalets EL. Update: clinically significant cytochrome P 450 drug interactions. Pharmacotherapy . 1998; 18:84-112. [PubMed 9469685]
298. Ortho-McNeil. Ortho-Novum® (norethindrone/ethinyl estradiol) and Modicon (northindrone/ethinyl estradiol) tablets prescribing information (dated May 1998). In: Physicians' desk reference. 55th ed. Montvale NJ: Medical Economics Company Inc; 2001:2363-70.
299. Parke-Davis. Estrostep® (norethindrone acetate and ethinyl estradiol) tablets prescribing information. Morris Plains, NJ; 2001 Jul.
300. Ortho-McNeil Pharmaceutical. Micronor® (norethindrone) tablets prescribing information. (dated 1998 June). In: Physicians' desk reference. 55th ed. Montvale, NJ: Medical Economics Company Inc; 2001:2344-6.
301. Parke -Davis. Loestrin® (norethindrone acetate and ethinyl estradiol) tablets prescribing information. (dated 1998 Apr). In: Physicians' desk reference. 53rd ed. Montvale NJ: Medical Economics Company Inc; 1999(Suppl A):A42-50.
303. Oelkers W, Berger V, Bolik A et al. Dihydrospirorenone, a new progestogen with antimineralocorticoid activity: effects on ovulation, electrolyte excretion, and the renin-aldosterone system in normal women. J Clin Endocrinol Metab . 1991; 73:837-42. [PubMed 1890155]
304. Oelkers W, Foidart JM, Dombrovicz N et al. Effects of a new oral contraceptive containing an antimineralocorticoid progestogen, drospirenone, on the renin-aldosterone system, body weight, blood pressure, glucose tolerance, and lipid metabolism. J Clin Endocrinol Metab . 1995; 80:1816-21. [PubMed 7775629]
305. Krattenmacher R. Drospirenone: pharmacology and pharmacokinetics of a unique progestogen. Contraception . 2000; 62:29-38. [PubMed 11024226]
306. Gilliam M, Elam G, Maloney JM et al. Acne treatment with a low-dose oral contraceptive. Obstet Gynecol . 2001; 97(4 Suppl 1):S9.
307. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-induced Osteoporosis. Recommendations for the prevention and treatment of gluococorticoid-induced osteoporosis: 2001 update. Arthritis Rheum . 2001; 44:1496-503. [PubMed 11465699]
308. Ortho-McNeil Pharmaceutical. Ortho Evra® (norelgestromin/ethinyl estradiol) transdermal system prescribing information. Raritan, NJ; 2008 Mar.
309. Organon. NuvaRing® (etonogestrel/ethinyl estradiol) vaginal ring prescribing information. West Orange, NJ; 2001.
310. Panel on Antiretroviral Guidelines for Adults and Adolescents of the Department of Health and Human Services (DHHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (January 29, 2008). From the US Department of Health and Human Services HIV/AIDS Information Services (HIV.gov) website. [Web]
311. Roumen FJME, Apter D, Mulders TMT et al. Efficacy, tolerability, and acceptability of a novel contraceptive vaginal ring releasing etonogestrel and ethinyl oestradiol. Hum Reprod . 2001; 16:469-75. [PubMed 11228213]
312. Timmer CJ, Mulders TM. Pharmacokinetics of etonogestrel and ethinylestradiol released from a combined contraceptive vaginal ring. Clin Pharmacokinet . 2000; 39:233-42. [PubMed 11020137]
313. Dittrich R, Parker L, Rosen JB et al. Transdermal contraception: evaluation of three transdermal norelgestromin/ethinyl estradiol doses in a randomized, multicenter, dose-response study. Am J Obstet Gynecol . 2002; 186: 15-20. [PubMed 11810078]
314. Abrams LS, Skee DM, Natarajan J et al. Pharmacokinetics of a contraceptive patch (Evra®/Ortho Evra®) containing norelgestromin and ethinyloestradiol at four application sites. Br J Clin Pharmacol . 2002; 53:141-6. [PubMed 11851637]
315. Abrams LS, Skee D, Natarajan J et al. Pharmacokinetic overview of Ortho Evra/Evra. Fertil Steril . 2002; 77(2 suppl 2):S3-12. [PubMed 11849630]
316. Abrams LS, Skee DM, Natarajan J et al. Pharmacokinetics of norelgestromin and ethinyl estradiol delivered by a contraceptive patch (Ortho Evra/Evra) under conditions of heat, humidity, and exercise. J Clin Pharmacol . 2001; 41:1301-9. [PubMed 11762557]
317. Smallwood GH, Meador ML, Lehinan JP et al. Efficacy and safety of a transdermal contraceptive system. Obstet Gynecol . 2001; 98(5 Part 1):799-805. [PubMed 11704172]
318. Marchbanks PA, McDonald JA, Wilson HG et al. Oral contraceptives and the risk of breast cancer. N Engl J Med . 2002; 346:2025-32. [PubMed 12087137]
319. Davidson NE, Helzlsouer KJ. Good news about oral contraceptives. N Engl J Med . 2002; 346:2078-9. [PubMed 12087145]
320. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53297 women with breast cancer and 100239 women without breast cancer from 54 epidemiological studies. Lancet . 1996; 347:1713-27. [PubMed 8656904]
321. Ortho-McNeil Pharmaceutical. Ortho Tri-Cyclen® Lo (norgestimate/ethinyl estradiol) tablets prescribing information. Raritan, NJ; 2002 Aug.
322. Duramed Pharmaceuticals. Seasonale® (levonorgestrel/ethinyl estradiol) tablets 0.15 mg/ 0.03 mg prescribing information. Pomona, NY; 2003 Sep.
323. Menon KVN. Shah V, Kamath PS. The Budd-Chiari syndrome. N Engl J Med . 2004; 350:578-85. [PubMed 14762185]
324. Raine TR, Harper CC, Rocca CH et al. Direct access to emergency contraception through pharmacies and effect on unintended pregnancy and STIs: a randomized controlled trial. JAMA . 2005; 293:54-62. [PubMed 15632336]
325. Litt IF. Placing emergency contraception in the hands of women. JAMA . 2005; 293:98-9. [PubMed 15632343]
326. American College of Obstetricians and Gynecologists. Statement of Vivian M. Dickerson, MD, President on JAMA emergency study. 2005 Jan 5. Press release.
327. FDA Statement. FDA takes action on Plan B: statement by FDA commissioner Lester M. Crawford. 2005 Aug 26. (From FDA web site. [Web]
328. FDA. FDA's decision regarding Plan B: questions and answers. 2004 May 7. From FDA web site. [Web]
329. Duramed Pharmaceuticals. Plan B® One-Step (levonorgestrel) 1.5 mg tablets prescribing information. Pomona, NY; 2009 Jul.
331. Duramed Pharmaceuticals. Seasonique® (levonorgestrel/ethinyl estradiol tablets 0.15 mg/ 0.03 mg and ethinyl estradiol 0.01 mg tablets) prescribing information. Pomona, NY; 2006 May.
332. Warner Chilcott. Loestrin® 24 Fe (norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets) prescribing information. Rockaway, NJ; 2006 Feb.
334. Jick SS, Kaye JA, Russmann S et al. Risk of nonfatal venous thromboembolism in women using a contraceptive transdermal patch and oral contraceptive containing norgestimate and 35 microg of ethinyl estradiol. Contraception . 2006; 73:223-8. [PubMed 16472560]
335. Anon. Three new oral contraceptives. Med Lett Drugs Ther . 2006; 48:77-8. [PubMed 17001297]
336. Edelman AB, Gallo MF, Jensen JT et al. Continuous or extended cycle versus cyclic use of combined oral contraceptives for contraception. Cochrane Database of Systematic Reviews . 2005; 3:CD004695.
337. Warner Chilcott. Femcon® Fe (norethindrone and ethinyl estradiol tablets, chewable and ferrous fumarate tablets) prescribing information. Rockaway, NJ; 2006 Sep.
338. Pearlstein TB, Bachmann GA, Zacur HA, Yonkers KA. Treatment of premenstrual dysphoric disorder with a new drospirenone-containing oral contraceptive formulation. Contraception . 2005; 72:414-21. [PubMed 16307962]
339. Wyeth. Lybrel® (90 mcg levonorgestrel and 20 mcg ethinyl estradiol) tablets prescribing and patient information. Philadelphia, PA; 2007 May.
340. Archer DF, Jensen JT, Johnson JV et al. Evaluation of a continuous regimen of levonorgestrel/ethinyl estradiol: phase 3 study results. Contraception . 2006; 74:439-45. [PubMed 17157099]
341. Yonkers KA, Brown C, Pearlstein TB et al. Efficacy of a new low-dose oral contraceptive with drospirenone in premenstrual dysphoric disorder. Obstet Gynecol . 2005; 106:492-501. [PubMed 16135578]
342. Bracken MB, Hellenbrand KG, Holford TR. Conception delay after oral contraceptive use: the effect of estrogen dose. Fertil Steril . 1990; 53:21-7. [PubMed 2295345]
343. Chasan-Taber L, Willett WC, Stampfer MJ et al. Oral contraceptives and ovulatory causes of delayed fertility. Am J Epidemiol . 1997; 146:258-65.
344. Hassan MA, Killick SR. Is previous use of hormonal contraception associated with a detrimental effect on subsequent fecundity? Hum Reprod . 2004; 19:344-51.
345. American College of Obstetricians and Gynecologists (ACOG) Committee Practice Bulletin. Emergency Contraception. Practice Bulletin No. 69. Washington, DC: American College of Obstetricians and Gynecologists; 2005 Dec.
346. American Academy of Pediatrics Committee on Adolescence, Policy statement: emergency contraception. Pediatrics . 2005; 116:1026-35. [Web]
347. American Academy of Pediatrics Committee on Adolescence, Policy statement: contraception and adolescents. Pediatrics . 2007; 120:1135-48.
348. Cheng L, Gülmezoglu AM, Piaggio G et al for the Cochrane Collaboration. Interventions for emergency contraception (review). Cochrane Database of Systematic Reviews . 2008, Issue 2. Art. No.: CD001324.
349. Polis CB, Schaffer K, Blanchard K et al for the Cochrane Collaboration. Advance provision of emergency contraception for pregnancy prevention (review). Cochrane Database of Systematic Reviews . 2007, Issue 2. Art. No.: CD005497.
350. World Health Organization. Department of Reproductive Health and Research. Medical eligibility criteria for contraceptive use. 3rd ed. Geneva, Switzerland: World Health Organization; 2004.
351. Cole JA, Norman H, Doherty M, Walker AM. Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users. Obstet Gynecol . 2007; 109:339-46. [PubMed 17267834]
352. Jick S, Kaye JA, Li L, Jick H. Further results on the risk of nonfatal venous thromboembolism in users of the contraceptive transdermal patch compared to users of oral contraceptives containing norgestimate and 35 microg of ethinyl estradiol. Contraception . 2007; 76:4-7. [PubMed 17586129]
353. Boston Collaborative Drug Surveillance Program. Postmarketing study of Ortho Evra® and levonorgestrel oral contraceptives in relation to non-fatal venous thromboembolism, ischemic stroke and myocardial infarction. From National Institute of Health. [Web]
354. Duramed Pharmaceuticals. LoSeasonique® (levonorgestrel/ethinyl estradiol tablets and ethinyl estradiol tablets) prescribing information. Pomona, NY; 2008 Oct. (
355. US Food and Drug Administration. FDA drug safety communication: Safety review of possible increased risk of blood clots with birth control pills containing drospirenone. Rockville, MD; 2011 May 31. From FDA website. Accessed 2011 Sep 13. [Web]
356. US Food and Drug Administration. FDA drug safety communication: Safety review update on the possible increased risk of blood clots with birth control pills containing drospirenone. Rockville, MD; 2011 Sep 26. From FDA website. Accessed 2011 Sep 27. [Web]
357. Parkin L, Sharples K, Hernandez RK et al. Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: nested case-control study based on UK General Practice Research Database. BMJ . 2011; 342:d2139.
358. Jick SS, Hernandez RK. Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data. BMJ . 2011; 342:d2151.
359. Seeger JD, Loughlin J, Eng PM et al. Risk of thromboembolism in women taking ethinylestradiol/drospirenone and other oral contraceptives. Obstet Gynecol . 2007; 110:587-93. [PubMed 17766604]
360. Dinger JC, Heinemann LA, Kühl-Habich D. The safety of a drospirenone-containing oral contraceptive: final results from the European Active Surveillance Study on oral contraceptives based on 142,475 women-years of observation. Contraception . 2007; 75:344-54. [PubMed 17434015]
361. Lidegaard O, Løkkegaard E, Svendsen AL et al. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ . 2009; 339:b2890. [PubMed 19679613]
362. van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP et al. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ . 2009; 339:b2921. [PubMed 19679614]
363. Brown DA, Vartan CM. Risk of venous thromboembolism with drospirenone-containing oral contraceptives. Am J Health Syst Pharm . 2011; 68:1003-10. [PubMed 21593228]
364. US Food and Drug Administration. FDA drug safety communication: birth control pills containing drospirenone: label change-products may be associated with a higher risk for blood clots. Rockville, MD; 2012 Apr 10. From FDA website. [Web]
365. Bayer HealthCare Pharmaceuticals Inc. Yasmin® (drospirenone/ethinyl estradiol) tablets prescribing information. Wayne, NJ; 2012 Apr.
366. Bayer HealthCare Pharmaceuticals Inc. Yaz® (drospirenone/ethinyl estradiol) tablets prescribing information. Wayne, NJ; 2012 Apr.
367. Bayer HealthCare Pharmaceuticals Inc. Beyaz® (drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium) tablets prescribing information. Wayne, NJ; 2012 Apr.
368. Bayer HealthCare Pharmaceuticals Inc. Safyral® (drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium) tablets prescribing information. Wayne, NJ; 2012 Apr.
369. Sidney S, Cheetham TC, Cooper WO et al. Combined hormonal contraceptives (CHCs) and the risk of cardiovascular disease endpoints. From FDA website. Accessed 2012 Sep 17. [Web]
370. Dinger J. Long-term active surveillance study for oral contraceptives (LASS). From NIH website. Accessed 2012 Sep 21. [Web]
371. Lidegaard O, Nielsen LH, Skovlund CW et al. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ . 2011; 343:d6423. [PubMed 22027398]
372. Dinger J, Assmann A, Möhner S et al. Risk of venous thromboembolism and the use of dienogest- and drospirenone-containing oral contraceptives: results from a German case-control study. J Fam Plann Reprod Health Care . 2010; 36:123-9. [PubMed 20659364]
373. US Food and Drug Administration. Updating external questions and answers: ongoing safety review of birth control pills containing drospirenone and a possible increased risk of blood clots. Rockville, MD; 2012 Apr 10. From FDA website. Accessed 2012 Sep 27. [Web]