Prescription Required
In stock
Manufacturer
MAYNE PHARMA IN
SKU
51862051006

brand trivora-28 tablet

Brand
$20.62 / blist pack
$27.49 / blist pack
$6.87 / blist pack
+ -
1,000 blist packs Available
Total Price:

Uses

Contraception

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. 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. 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. 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.

Because the pharmacokinetic profile for the transdermal contraceptive system containing ethinyl estradiol and norelgestromin (Ortho Evra) differs from the profile for oral contraceptive preparations(see Pharmacokinetics: Absorption), 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. Increased exposure to estrogen may increase the risk of certain adverse effects (e.g., venous thromboembolism).(See Thromboembolic Disorders in Cautions: Cardiovascular Effects.)

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. (See Pharmacology: Other Effects.)

For information on parenteral use of fixed combinations of medroxyprogesterone acetate and estradiol cypionate (e.g., Lunelle),

Postcoital Contraception

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). If taken soon enough after intercourse (i.e., within 72-120 hours), the combination regimen can prevent not terminate pregnancy; therefore, the regimen is contraceptive not abortifacient.

Several regimens employing high-dose combinations of ethinyl estradiol and norgestrel or levonorgestrel have been used safely and effectively for postcoital contraception. 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. 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. Raw pregnancy (failure) rates in trials employing such regimens have ranged from 0.2-7.4%. 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. 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. 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. Because of study limitations of this pooled analysis, it is likely that true efficacy rates are higher than this estimate, perhaps exceeding 80%. However, postcoital (emergency) contraceptive regimens are not as effective as most other forms of long-term contraception. The efficacy of postcoital regimens employing lower estrogen/progestin doses currently is not known.

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.

To prevent pregnancy, oral estrogen-progestin combination therapy ideally should begin within 72 hours following coitus. Studies show that emergency contraception is moderately effective when the first dose is administered up to 120 hours after unprotected intercourse. Postcoital contraceptive efficacy diminishes as the time period between intercourse and administration of the combination increases, with the regimen becoming completely ineffective by day 6 or 7, when implantation usually occurs.

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. 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. 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). Postcoital contraceptive regimens should not be used as a routine method of contraception. Women should be informed that postcoital contraceptives do not protect against human immunodeficiency virus (HIV) infection or other sexually transmitted diseases. 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. Women who request emergency contraceptives repeatedly should be informed about other contraceptive options.

The American College of Obstetricians and Gynecologists (ACOG), other experts, and some states (e.g., Alaska, California, Hawaii, Maine, New Mexico, Washington) 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, 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.

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. If pregnancy has already occurred, there is little, if any, evidence that postcoital regimens will adversely affect the fetus or pregnancy.(See Cautions: Pregnancy, Fertility, and Lactation.) 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). 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.

For the use of progestin-only therapy as a postcoital contraceptive, .

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. 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. 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). Folate supplementation should be maintained if a woman discontinues this contraceptive because of pregnancy.

Acne Vulgaris

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. 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.

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.

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. 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. In these studies, ethinyl estradiol in combination with drospirenone was found to be superior to placebo in improving symptoms associated with this disorder. 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.

Other Uses

Estrogen-progestin preparations have been used for the treatment of endometriosis or dysfunctional uterine bleeding.

Dosage and Administration

Administration

Estrogen-progestin combination contraceptives are administered orally, intravaginally, and percutaneously by topical application of a transdermal system to the skin.

Contraception

Oral Administration

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.

Chewable tablets may be swallowed whole or chewed and consumed with 240 mL of liquid.

Intravaginal Administration

Patients receiving the vaginal contraceptive ring containing ethinyl estradiol and etonogestrel (NuvaRing) should be carefully instructed in the use of the vaginal ring. To obtain optimum results, patients also should be given a copy of the patient information provided by the manufacturer. 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. 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. 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.

Transdermal Administration

Women receiving the transdermal contraceptive containing ethinyl estradiol and norelgestromin (Ortho Evra) should be instructed in the use of the transdermal system. To obtain optimum results, women also should be given a copy of the patient information provided by the manufacturer. 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. 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. The application site should not be oily, damaged, or irritated. The transdermal system should not be applied to the breasts or to areas where tight clothing may cause the system to be rubbed off. 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. 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. 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.

Postcoital Contraception

Oral Administration

Postcoital contraceptive regimens usually consist of 2-5 tablets per dose administered 12 hours apart. 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. 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). 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.

Because the high dosage in the combination regimens may cause severe nausea and vomiting in a substantial proportion of women, 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. Administering the dose with food is not effective in reducing adverse GI effects (i.e., nausea). 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.

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. 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.

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.

Dosage

Contraception

Before initiating therapy, women receiving estrogen-progestin contraceptives should be given a copy of the patient labeling for the drugs.

Oral Dosage

Estrogen-progestin oral contraceptives are usually classified according to their formulation: those monophasic preparations containing 50 mcg of estrogen,those monophasic preparations containing less than 50 mcg of estrogen (usually 20-35 mcg),those containing less than 50 mcg of estrogen with 2 sequences of progestin doses (biphasic),those containing less than 50 mcg of estrogen with 3 sequences of progestin doses (triphasic), andthose containing 3 sequences of estrogen (e.g., 20, 30, 35 mcg) with a fixed dose of progestin (estrophasic).

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. 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.

One fixed-combination continuous-regimen (noncyclic) oral contraceptive (i.e., Lybrel) is available as a 28-day dosage preparation containing 28 hormonally active tablets.

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. A back-up method of contraception is not needed if the first dosage cycle is initiated on the first day of the menstrual cycle. 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.

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. 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. 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''. 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.

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. 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.

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. (See Thromboembolic Disorders in Cautions: Cardiovascular Effects.)

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. (See Cautions: Genitourinary Effects.) For information on the use of oral contraceptives when a menstrual period has been missed, see Cautions: Pregnancy, Fertility, and Lactation.

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. 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. 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. 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. 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. 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. 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. A back-up contraceptive method is not required during the fourth week as a result of missed inactive tablets. 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). 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.

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. 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. 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. (See Cautions: Pregnancy, Fertility, and Lactation.)

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. 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. 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. Administration of the extended-cycle preparation usually begins on the first Sunday after or on which bleeding begins. A back-up method of contraception (e.g., condom, spermicide) should be employed for 7 days following initiation of therapy. Withdrawal bleeding usually occurs during the 7 days after the last estrogen/progestin tablet. Repeat dosage cycles begin on the same day of the week (Sunday) as the initial cycle. 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.

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. Additional contraceptive measures are not necessary if only one tablet is missed. 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. 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. 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. 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. 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. A back-up contraceptive method is not required if the patient missed inert or estrogen-containing tablets. 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. 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.

In nonlactating postpartum women, fixed-combination extended-cycle oral contraceptives may be started no earlier than 28 days after delivery. 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.

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). Therefore, women using this preparation should expect no withdrawal menstruation-like bleeding; uterine bleeding and/or spotting does occur in some women. 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. A back-up method of contraception is not needed if the oral contraceptive is started on the first day of the menstrual cycle. 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. 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. Women switching from a progestin-only implant should start the continuous-regimen oral contraceptive on the same day that the implant is removed. 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. 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.

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). 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. 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. 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. 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. 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.

In nonlactating postpartum women, the fixed-combination continuous-regimen oral contraceptive may be started no earlier than 28 days after delivery. In addition, the continuous regimen oral contraceptive may be started no earlier than 28 days after a second-trimester abortion. A back-up method of contraception should be used until the patient has taken the oral contraceptive for 7 days. Women may start the continuous-regimen oral contraceptive immediately following a complete first-trimester abortion; a back-up method of contraception is not needed.

Intravaginal Dosage

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. 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. 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. After a 1-week ring-free period, a new ring is inserted on the same day of the week as in the previous cycle. Withdrawal bleeding usually occurs within 2-3 days after removal of the ring. For contraceptive effectiveness, a new ring must be inserted 1 week after the previous ring was removed even if menstrual bleeding is not finished.

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. 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. 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. 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). 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. 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. 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.

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. 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. 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.

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. 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.

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.

Transdermal Dosage

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. 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. 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. (See Pharmacokinetics: Absorption and see the introductory discussion under Cautions.)

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. 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. A back-up method of contraception is not needed if the first system is applied on the first day of the menstrual cycle. 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. If there is no withdrawal bleeding within 5 days of the last hormonally active tablet, pregnancy must be ruled out. 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. If more than 7 days elapse after receiving the last hormonally active tablet, the possibility of ovulation and conception should be considered.

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. 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. 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. 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.

Women may start using the transdermal contraceptive system immediately after a first-trimester abortion; a back-up method of contraception is not needed. 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.

Postcoital Contraception

Oral Dosage

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. 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. 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. 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. Because postcoital efficacy diminishes as the time between intercourse and initiation of estrogen-progestin combination therapy increases, such therapy should be initiated as soon as possible but preferably within 72 hours following unprotected intercourse. If necessary, the first dose can be given up to 120 hours after unprotected intercourse. 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.

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.

Table 1. Dosage of estrogen-progestin combinations for postcoital contraception
Estrogen-progestin combination formulation [brand name] Number and color of tablets per dose
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)

Dose is administered initially and then repeated 12 hours later

Contraception and Folate Supplementation

Oral Dosage

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.

Acne Vulgaris

Oral Dosage

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.

Premenstrual Dysphoric Disorder

Oral Dosage

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.(See Conventional-cycle Oral Contraceptives under Dosage: Contraception, in Dosage and Administration.)

Cautions

The potential risks of estrogen-progestin contraceptive use have been established in women of reproductive age. The risks should be identical for postpubertal adolescents under 16 years of age and users 16 years of age or older. Estrogen-progestin combination contraceptives including short-term, high-dose postcoital contraceptives are not indicated before menarche.

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. Increased exposure to estrogen may increase the risk for adverse effects.

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.

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. Adverse effects similar to those with oral estrogen-progestin contraceptives generally are expected with vaginal estrogen-progestin contraceptives.

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). There is some evidence that oral contraceptives containing desogestrel may be associated with an increased risk of nonfatal venous thrombosis. (See Thromboembolic Disorders in Cautions: Cardiovascular Effects.)

Limited data are available concerning the risk of using short-course, high-dose estrogen-progestin combinations for emergency contraception. No serious or long-term complications have been associated with such postcoital regimens in Europe, where experience is extensive. 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).

GI Effects

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.

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. 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).

Other adverse GI effects include vomiting, abdominal cramps, abdominal pain, bloating, diarrhea, constipation, and inflammatory bowel disease. Gingivitis and dry socket also have been reported. Changes in appetite and changes in weight also may occur.

Dermatologic Effects

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. 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. 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.

Cardiovascular Effects

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.

Elevated Blood Pressure

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.

Thromboembolic Disorders

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. 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. 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.(See Pharmacokinetics: Absorption.) Increased exposure to estrogen may increase the risk of certain adverse effects (e.g., VTE). 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. 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). 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). 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). 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).

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.

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). 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). 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. Some experts have recommended that estrogen-progestin combinations containing desogestrel or gestodene not be prescribed routinely for prevention of conception in women; however, other clinicians state that further analysis of data is needed for such a recommendation. 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. 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.

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. 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. These studies reported that the risk of VTE in such women ranged from no increase to a threefold increase in risk. 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. 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. 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. 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.(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. 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. 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. 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. At this time, the FDA has concluded that the risk of VTE may be higher for such oral contraceptives. The FDA will continue to communicate any new safety information as it becomes available.

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. The use of estrogen-progestin contraceptives also is associated with an increased risk of stroke in women with other underlying risk factors. 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). 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. (See Effects on Lipids and Lipoproteins, in Cautions: Endocrine and Metabolic Effects.)

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. (See Cautions: Precautions and Contraindications.)

Other Cardiovascular Effects

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. (See Cautions: Precautions and Contraindications.) 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.

Effects on Glucose

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. 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.

Effects on Thyroid

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. (See Laboratory Test Interferences.)

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.

Hepatic Effects

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. 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.

Genitourinary Effects

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) (see Pregnancy, in Cautions: Pregnancy, Fertility, and Lactation), 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. Irregular bleeding occurs most often during the first few 91-day cycles. 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. 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. 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.

Use of extended-cycle oral contraceptive preparations is associated with fewer menstrual symptoms than use of conventional-cycle oral contraceptive preparations. 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.

While use of a continuous-regimen (noncyclic) estrogen-progestin oral contraceptive (Lybrel) eliminates withdrawal bleeding, irregular bleeding and/or spotting occurs in some women. 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.

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.

Nervous System Effects

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.

Ocular Effects

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. Cataracts have also occurred during oral contraceptive use but have not been directly attributed to the drugs.

Hematologic Effects

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.

Other Adverse Effects

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. The risk of thrombotic events is even higher in women with other risk factors for these events. 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. 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. (See Pharmacology: Other Effects.)

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.

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. 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. No serious or long-term complications have been associated with such postcoital contraceptive regimens in Europe, where experience is extensive. 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.

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. 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.

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. Oral contraceptive combinations containing drospirenone should be discontinued if an arterial or venous thrombotic event occurs during therapy. Women currently receiving an oral contraceptive combination containing drospirenone should be informed of the potential risk of thromboembolic events. 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. Known risk factors for development of VTE include smoking, obesity, family history, and other factors that contraindicate the use of oral contraceptive combinations. Patients should discuss their risk of VTE with their clinician before deciding which contraceptive method to use. The risk of thromboembolic disease associated with oral contraceptive use gradually disappears after such therapy is discontinued. However, the FDA states that patients should not discontinue oral contraceptives containing drospirenone without consulting a clinician.

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. The risk of VTE in women receiving estrogen-progestin oral contraceptives is estimated to be 3-9 per 10,000 woman-years. 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. The risk of VTE is highest during the first year of oral contraceptive use. 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. 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. 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.

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. 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.(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.

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.

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. 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. The risk of thromboembolism decreases while the risk of ovulation increases after the first 3 weeks postpartum.

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). 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.

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. The clinician and the woman with high body weight should discuss the individual needs of such a patient when choosing an appropriate contraceptive option.

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.

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.

Pediatric Precautions

Safety and efficacy of estrogen-progestin contraceptives have been established in women of reproductive age. Safety and efficacy are expected to be identical for postpubertal adolescents under 16 years of age and users 16 years of age or older. 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. Estrogen-progestin contraceptives are not indicated before menarche.

Geriatric Precautions

Oral contraceptives have not been evaluated in women 65 years of age and older and are not indicated in this population.

Mutagenicity and Carcinogenicity

Chromosomal abnormalities determined in peripheral lymphocytes have been increased in women receiving oral contraceptives compared with nonusers.

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.

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. 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.

Cervical Cancer

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. These data revealed no evidence of increased risk of invasive cervical cancer in users compared with nonusers. The FDA recommends that all estrogen-progestin contraceptive users be monitored carefully with physical examinations and Papanicolaou tests, at least yearly. (See Cautions: Precautions and Contraindications.)

Endometrial Cancer

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. This decreased risk of endometrial cancer was not evident in women who had used oral contraceptives for less than 12 months.

Ovarian Cancer

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. 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. 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.

Breast Cancer

Many studies have shown no increased risk of breast cancer in women receiving oral contraceptives or estrogens. Some studies, however,

Drug Interactions

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. Metabolism of estrogens is mediated by the CYP3A4 isoenzyme, and the possibility exists that drugs that induce this isoenzyme may reduce ethinyl estradiol concentrations.

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. 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. 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.

Estrogens are inhibitors of the CYP enzyme and may alter the pharmacokinetics of drugs metabolized by this isoenzyme.

Anti-infective Agents

Antiretroviral Agents

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. 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. For additional information, see the individual monographs in 8:18:08 Antiretroviral Agents.

Other Anti-infective Agents

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. While the clinical importance of these findings is unknown, the efficacy of the contraceptive vaginal ring is not expected to be affected. The effects of long-term administration of miconazole nitrate vaginal suppositories in women using the contraceptive vaginal ring are not known.

Fluconazole, itraconazole and ketoconazole also may increase plasma concentrations of contraceptive steroids.

Concurrent use of oral contraceptives and troleandomycin may increase the risk of cholestatic jaundice; therefore, the drugs should be used together cautiously.

Benzodiazepines

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.

β-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.

Corticosteroids

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. 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.

Other Drugs

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.

Increased plasma concentrations of cyclosporine and theophylline have been observed when these drugs were used concomitantly with oral contraceptives. Ascorbic acid or acetaminophen may increase plasma concentrations of some synthetic estrogens. 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. 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.

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. 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. 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.

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. The effects of long-term vaginal administration of nonoxynol 9 spermicide gel in women using the contraceptive vaginal ring are not known.

Pharmacokinetics

Absorption

Oral Administration

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. 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%. 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.

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. 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. 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.

Vaginal Administration

Ethinyl estradiol and etonogestrel are absorbed systemically through the mucous membrane. 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. 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. Following vaginal administration of the ring, bioavailability appears to be about 56% for ethinyl estradiol and 100% for etonogestrel.

Transdermal Administration

Ethinyl estradiol and norelgestromin are also absorbed systemically through the skin. 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). 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. Serum concentrations generally are consistent from all studies and application sites (i.e., abdomen, buttock, upper outer arm, upper torso). 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. 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. 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.

The pharmacokinetic profile for the transdermal contraceptive system containing ethinyl estradiol and norelgestromin (Ortho Evra) differs from the profile for oral contraceptive preparations. 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. 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).

Distribution

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. Drospirenone is about 97% protein bound, presumably to albumin. Etonogestrel is about 32% bound to SHBG and 66% bound to albumin. Norelgestromin is reportedly more than 97% bound to serum proteins (mainly albumin). Norgestimate, norelgestromin, drospirenone, and ethinyl estradiol do not appear to bind to SHBG. 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.

Elimination

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). 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. Plasma clearance of norethindrone and ethinyl estradiol each is about 0.4 L/hour per kg. Serum concentrations of norgestimate generally are below the lower detection limits of assay within 5 hours of single or multiple oral dosing, and determination of half-life of the drug may not be accurate. An elimination half-life of 12-30 hours has been reported for 17-acetyl norgestimate (an active metabolite of norgestimate). 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.

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.

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. 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. 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. 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. 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. The manufacturers state that drospirenone is metabolized only to a minor extent in vitro, mainly by CYP3A4. At least 20 metabolites have been detected in urine or feces.

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.

Write Your Own Review
You're reviewing:TRIVORA-28 TABLET
Your Rating