Estrogen-Progestin Combinations (Monograph)

Drug class: Contraceptives

Introduction

Contraceptive combinations containing estrogenic and progestinic steroids.^a

Uses for Estrogen-Progestin Combinations

Contraception

Prevention of conception in women.^a

Postcoital Contraception

Prevention of conception after unprotected intercourse (including known or suspected contraceptive failure) as an emergency contraceptive^{† [off-label]} (“morning-after” pills).^{254 255 257 258 259 261 262 264 265 345 346 347 348 349} Postcoital (emergency) contraceptive regimens are not as effective as most other forms of long-term contraception and should not be used as routine forms of contraception.^{345 346}

An emergency contraceptive regimen employing a progestin alone (levonorgestrel) appears to be more effective and better tolerated than a common estrogen-progestin emergency contraceptive (“Yuzpe”) regimen when the regimens are initiated within 72 hours of unprotected intercourse, and therefore, generally is preferred when readily available.^{345 346 347 348}

Contraception and Folate Supplementation

Beyaz, Safyral: Prevention of conception while also increasing folate concentrations (to reduce risk of fetal neural tube defects if pregnancy occurs during or shortly after therapy).^{367 368} US Preventive Services Task Force recommends that women of childbearing age receive supplemental folic acid at a dosage of ≥0.4 mg daily.^{367 368} Consider other folate supplementation that a woman may be taking before prescribing this drug combination.^{367 368} Ensure that folate supplementation is maintained if the contraceptive is discontinued due to pregnancy.^{367 368}

Acne Vulgaris

Ortho Tri-Cyclen, Estrostep: Treatment of moderate acne vulgaris in females ≥15 years of age who have no known contraindications to oral contraceptive therapy, desire contraception, have achieved menarche, and are unresponsive to topical anti-acne medication.^{299 321} Estrostep should be used for the treatment of acne vulgaris only in women who desire oral contraception and plan to take the drug for at least 6 months.²⁹⁹

Yaz, Beyaz: Treatment of moderate acne vulgaris in females ≥14 years of age who have no known contraindications to oral contraceptive therapy, desire oral contraception, and have achieved menarche.^{366 367}

Premenstrual Dysphoric Disorder

Yaz, Beyaz: Management of premenstrual dysphoric disorder in women who desire oral contraception.^{338 341 366 367}

Estrogen-Progestin Combinations Dosage and Administration

Administration

Administered orally, intravaginally, or percutaneously by topical application of a transdermal system to the skin.^a

Oral Administration

Contraception

Take as near as possible to the same time each day (i.e., at regular 24-hour intervals) to ensure maximum contraceptive efficacy.^a

Take with or after the evening meal or at bedtime to minimize nausea.^a

Vomiting or diarrhea may decrease absorption of oral contraceptives and potentially result in treatment failures; in such instances, use a back-up method of contraception (e.g., condoms, foam, sponge) until the next clinician contact.^{295 296 298 299 301}

Chewable tablets may be swallowed whole or chewed and consumed with 240 mL of liquid.³³⁷

Available in a mnemonic dispensing package designed to aid the user in complying with the prescribed dosage schedule.^a

Postcoital Contraception

Administer first contraceptive dose as soon as possible but preferably within 72 hours following unprotected sex; repeat dose 12 hours later.^{254 255 257 258 260 261 262 264 265 345 346 347} Schedule 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 pose a problem of compliance for heavy sleepers).^{265 275 282 284}

Most data support administration of the first dose up to 120 hours after unprotected intercourse if necessary, but efficacy decreases as initiation of contraception becomes more remote from unprotected intercourse.^{345 346 347} Efficacy not established if administered >120 hours after unprotected intercourse.^{345 346}

Consider use of an antiemetic 1 hour before the first dose.^{254 255 257 258 259 260 261 262 264 265 282 284 285 286 345} The high dosage in the combination regimens may cause severe nausea and vomiting.^{254 255 257 258 260 261 262 264 265 285} Food not effective in reducing adverse GI effects (i.e., nausea).^{345 346}

Consider repeating a dose if breakthrough vomiting occurs within 2 hours after administration.³⁴⁵

Vaginal Administration

The vaginal contraceptive ring (NuvaRing) is inserted into the vagina by the patient; the exact position of the ring inside the vagina is not critical for its proper functioning.³⁰⁹

If the ring is accidentally expelled, rinse with cool or lukewarm water and reinsert it or, if necessary, insert a new ring as soon as possible; in either case, the administration schedule employed should be continued.³⁰⁹

If the contraceptive ring is removed from the vagina for longer than 3 hours, use a back-up method of contraception (e.g., condoms, spermicides) until the ring has been used continuously for 7 days.³⁰⁹

Topical Administration

Apply transdermal system to a clean and dry area of intact skin on the buttock, abdomen, upper outer arm, or upper torso by firmly pressing the system with the adhesive side touching the skin.³⁰⁸ Press system firmly in place with the palm of the hand for about 10 seconds; ensure good contact, especially around the edges.³⁰⁸ Do not apply to sites that are oily, damaged, or irritated.³⁰⁸ Do not apply transdermal system to the breasts or to areas where tight clothing may cause the system to be rubbed off.³⁰⁸

If the system inadvertently gets detached and is removed for less than one day, reapply the system or, if necessary, apply a new system (if the system is no longer sticky); in either case, the application schedule employed should be continued.³⁰⁸

If the system is removed for longer than 1 day or for an unknown duration, apply a new system immediately and start a new 4-week cycle; use a back-up method of contraception (e.g., condoms, spermicides, diaphragm) for the first week of the new cycle.³⁰⁸

Dosage

The smallest dosage of estrogen and progestin compatible with a low failure rate and the individual needs of the woman should be used.^a

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.^a

Estrogen-progestin oral contraceptives are usually classified according to their formulation:

• those monophasic preparations containing 50 mcg of estrogen,

• those monophasic preparations containing <50 mcg of estrogen (usually 20–35 mcg),

• those containing <50 mcg of estrogen with 2 sequences of progestin doses (biphasic),

• those containing <50 mcg of estrogen with 3 sequences of progestin doses (triphasic), and

• those containing 3 sequences of estrogen (e.g., 20, 30, 35 mcg) with a fixed dose of progestin (estrophasic).

Oral contraceptives usually are described in terms of their estrogen content, although the progestin content of the formulations also varies.^a 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.^a 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.^a

Biphasic oral contraceptives contain 2 sequentially administered, fixed combinations of hormones per dosage cycle.^a The first sequence consists of tablets containing a fixed combination of low-dose estrogen and low-dose progestin, and the second sequence consists of tablets containing a fixed combination of low-dose estrogen and higher-dose progestin.^a Biphasic oral contraceptives are not the same as previously available “sequential” oral contraceptives, which consisted of an estrogen alone for the first sequence.^a

Triphasic oral contraceptives contain graduated sequences of progestin or estrogen per dosage cycle.^{294 299} With most commercially available triphasic oral contraceptives, 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.^a 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 or low but slightly higher-dose estrogen and higher-dose progestin, and the third sequence consists of tablets containing low-dose estrogen and either an even higher-dose progestin or low-dose progestin.^a

Estrophasic oral contraceptives are triphasic preparations in which the estrogen component progressively increases with each sequence.^{294 299}

Fixed-combination, conventional-cycle oral contraceptives are available as 21- or 28-day dosage preparations.^a Some 28-day preparations contain 21 hormonally active tablets and 7 inert or ferrous fumarate-containing tablets.^a Other 28-day preparations contain 24 hormonally active tablets and 4 inert or ferrous fumarate-containing tablets.^{332 366}

One monophasic, fixed-combination, extended-cycle oral contraceptive (e.g., Seasonale) is available as a 91-day dosage preparation containing 84 hormonally active tablets and 7 inert tablets.³²² Other extended-cycle oral contraceptive preparations (e.g., LoSeasonique, Seasonique) are available as 91-day preparations with 84 hormonally active tablets containing estrogen/progestin and 7 tablets containing low-dose estrogen.^{331 354}

One fixed-combination, continuous-regimen (noncyclic) oral contraceptive (i.e., Lybrel) is available as a 28-day dosage preparation containing 28 hormonally active tablets.³³⁹

The transdermal system (Ortho Evra) is applied topically in a cyclic regimen using a 28-day cycle.³⁰⁸

The vaginal contraceptive ring (NuvaRing) is intended to be used for 1 cycle, which consists of a 3-week period of continuous use of the ring followed by a 1-week ring-free period.³⁰⁹

Adults

Contraception

Oral (21- or 28-day conventional-cycle preparations)

Start on the first Sunday after or on which menstrual bleeding begins or on the first day of the menstrual cycle.^a

If the first dose is on the first Sunday on or after menstrual bleeding starts, use a back-up method of contraception (e.g., condoms, foam, sponge) for 7 days following initiation of oral contraceptive therapy.^{236 298 295 296 298 299 301 332 337 366} If the first dose is on the first day of the menstrual cycle, a back-up method of contraception is not necessary.^{236 298 295 296 298 299 301}

With 21-day conventional-cycle preparations, take 1 estrogen/progestin tablet once daily for 21 consecutive days, followed by 7 days without tablets.^a Begin repeat dosage cycles on the eighth day after the last hormonally active tablet (i.e., on the same day of the week as the initial cycle).^a

With 28-day conventional-cycle preparations containing 21 hormonally active tablets, take 1 estrogen/progestin tablet once daily for 21 consecutive days, followed by inert tablets or ferrous fumarate tablets for 7 days.^a Begin repeat dosage cycles on the eighth day after the last hormonally active tablet (i.e., on the same day of the week as the initial cycle).^a

With 28-day conventional-cycle preparations containing 24 hormonally active tablets, take 1 estrogen/progestin tablet once daily for 24 consecutive days, followed by inert tablets or ferrous fumarate tablets for 4 days.^{332 366} Begin repeat dosage cycles on the fifth day after the last hormonally active tablet (i.e., on the same day of the week as the initial cycle).^{332 366}

When 1 estrogen/progestin tablet of a conventional-cycle oral contraceptive is missed, take the missed tablet as soon as it is remembered, followed by resumption of the regular schedule.^a Additional contraceptive methods are not necessary if only 1 tablet is missed.^{295 296 298 299 301 321 332 337 366}

When 2 estrogen/progestin tablets are missed during the first 1 or 2 weeks of the cycle, take the 2 missed tablets as soon as they are remembered, take 2 tablets the next day, then resume the regular schedule.^{295 296 298 299 301 321 332 337 366} If 2 consecutive estrogen/progestin tablets are missed during the third or fourth week of a dosage cycle that was initiated on the first day of the menstrual cycle, discard the remainder of the tablets in the pack for that cycle and start a new dosage cycle the same day.^{295 296 298 299 301 321 332 337 366} If 2 consecutive estrogen/progestin tablets are missed during the third or fourth week of a dosage cycle that was initiated on the first Sunday on or after menstruation started, continue to take 1 tablet daily until Sunday, then discard the remainder of the tablets for that cycle and start a new dosage cycle that same day.^{295 296 298 299 301 321 332 337 366} When 2 or more estrogen/progestin tablets are missed on consecutive days, a back-up method of contraception should be used for each sexual encounter until a hormonally active tablet has been taken for 7 consecutive days.^{321 332 337 366}

If 3 or more consecutive estrogen/progestin tablets are missed during a dosage cycle that was initiated on the first day of the menstrual cycle, discard the remainder of the tablets in that cycle and start a new dosage cycle the same day.^{295 296 298 299 301 321 332 337 366} If 3 or more consecutive estrogen/progestin tablets are missed during a dosage cycle that was initiated on the first Sunday on or after menstruation started, take 1 tablet daily until Sunday, then discard the remainder of the tablets for that cycle and start a new dosage cycle that same day.^{295 296 298 299 301 321 332 337 366} A back-up method of contraception should be used for each sexual encounter until a hormonally active tablet has been taken for 7 consecutive days.^{321 332 337 366}

During week 4 of a 28-day dosage cycle, any inactive or ferrous fumarate tablets that are missed should be discarded; continue to take the remaining tablets until the cycle is finished.^{295 296 298 299 301 332 337 366} A back-up contraceptive method is not required during the fourth week as a result of missed inactive or ferrous fumarate tablets.^{295 296 298 299 301 332 337 366}

With 28-day contraceptive cycles, a new cycle of tablets should be started the day after taking the last tablet of the previous 28-day dosage cycle (i.e., no days without tablets).^{295 296 298 299 301 332 337 366}

If unsure of what drug regimen to take as a result of missed tablets, use a back-up method of contraception for each sexual encounter and take 1 estrogen/progestin tablet daily until the next clinician contact.^{295 296 298 299 301 321 332 337 366}

Oral (91-day extended-cycle preparations)

Start on the first Sunday after or on which bleeding begins.^{322 331 354} Use a back-up method of contraception (e.g., condom, spermicide) for 7 days following initiation of therapy.^{322 331 354}

Take 1 estrogen/progestin tablet daily for 84 days, followed by inert tablets or tablets containing 10 mcg of estrogen for 7 days.^{322 331 354} Repeat dosage cycles begin on the same day of the week (Sunday) as the initial cycle.^{322 331 354} If a repeat cycle is started later than the scheduled day, use a back-up method of contraception until an estrogen/progestin tablet has been taken for 7 consecutive days.^{322 331 354}

When 1 estrogen/progestin tablet is missed, take the missed tablet as soon as it is remembered, followed by resumption of the regular schedule.^{322 331 354} Additional contraceptive measures are not necessary if only one tablet is missed.^{322 331 354}

When 2 estrogen/progestin tablets are missed, take the 2 missed tablets as soon as they are remembered, 2 tablets the next day, then resume the regular cycle.^{322 331 354} Use a back-up method of contraception until an estrogen/progestin tablet has been taken for 7 consecutive days.^{322 331 354}

When 3 or more consecutive estrogen/progestin tablets are missed, continue to take 1 tablet daily; the missed tablets should be discarded.^{322 331 354} Use a back-up method of contraception until an estrogen/progestin tablet has been taken for 7 consecutive days.^{322 331 354}

If unsure of what drug regimen to take as a result of missed tablets, use a back-up method of contraception for each sexual encounter, and take 1 tablet daily until the next clinician contact.^{322 331 354}

Discard inert tablets or estrogen-containing tablets that are missed; continue to take the remaining tablets until the cycle is finished.^{322 331 354} If inert tablets or estrogen-containing tablets are missed, a back-up contraceptive method is not required.^{322 331 354}

Oral (continuous-regimen [noncyclic] preparation)

Women who did not use hormonal contraception in the preceding month: Start on the first day of the menstrual cycle.³³⁹ If the first dose is on the first day of the menstrual cycle, a back-up method of contraception is not necessary.³³⁹

Women switching from cyclic estrogen-progestin oral contraceptives: Start on the first day of withdrawal bleeding, within 7 days of the last hormonally active tablet.³³⁹ A back-up method of contraception is not needed.³³⁹

Women switching from progestin-only oral contraceptives: Start on the day after the last progestin tablet.³³⁹ Use a back-up method of contraception (e.g., condom, spermicide) until an estrogen/progestin tablet has been taken for 7 consecutive days.³³⁹

Women switching from a progestin-only implant: Start on the day that the implant is removed.³³⁹ Use a back-up method of contraception until an estrogen/progestin tablet has been taken for 7 consecutive days.³³⁹

Women switching from a progestin-only contraceptive injection: Start on the day that the next contraceptive injection would have been due.³³⁹ Use a back-up method of contraception until an estrogen/progestin tablet has been taken for 7 consecutive days.³³⁹

Take 1 estrogen/progestin tablet each day and continue daily without interruption.³³⁹

When 1 tablet is missed, take the missed tablet as soon as it is remembered, then resume the regular schedule (2 tablets may be taken on the same day).³³⁹ Use a back-up method of contraception until an estrogen/progestin tablet has been taken for 7 consecutive days.³³⁹

When 2 tablets are missed and the missed doses are remembered on the day of the second missed dose, take the 2 missed tablets as soon as remembered, then resume the regular schedule.³³⁹ When the 2 tablets are missed and the missed doses are remembered on the day after the second missed dose, take the 2 missed tablets as soon as remembered, take 2 tablets the next day, then resume the regular schedule.³³⁹ Use a back-up method of contraception until an estrogen/progestin tablet has been taken for 7 consecutive days.³³⁹

When 3 or more tablets are missed, contact clinician and continue to take 1 tablet daily until clinician contact.³³⁹ Use a back-up method of contraception until an estrogen/progestin tablet has been taken for 7 consecutive days.³³⁹

If unsure of what drug regimen to take as a result of missed tablets, use a back-up method of contraception for each sexual encounter.³³⁹

Nonlactating postpartum women may start the fixed-combination, continuous-regimen oral contraceptive no earlier than 28 days after delivery; a back-up method of contraception is needed until an estrogen/progestin tablet has been taken for 7 consecutive days.³³⁹

Women may start the continuous regimen immediately after a complete first-trimester abortion; a back-up method of contraception is not needed.³³⁹

Women may start the continuous regimen no earlier than 28 days after a second-trimester abortion; a back-up method of contraception is needed until an estrogen/progestin tablet has been taken for 7 consecutive days.³³⁹

Vaginal

To initiate therapy in women who did not use hormonal contraception in the preceding month, insert the vaginal contraceptive ring (NuvaRing) on or before day 5 of the cycle.³⁰⁹ During the first cycle, use a back-up method of contraception (e.g., condom, spermicide) until the vaginal ring has been used continuously for 7 days.³⁰⁹

After 3 weeks, remove the vaginal ring on the same day of the week as it was inserted and at about the same time of day.³⁰⁹ For contraceptive effectiveness, insert a new vaginal ring 1 week after the previous vaginal ring is removed even if menstrual bleeding is not finished.³⁰⁹

Women switching from estrogen-progestin oral contraceptives: Insert the vaginal ring within 7 days of the last hormonally active tablet and no later than the day that a new oral contraceptive cycle would have been started; a back-up method of contraception is not needed.³⁰⁹

Women switching from progestin-only oral contraceptives: Insert the vaginal ring on any day of the month (without skipping any day between receiving the last progestin oral contraceptive and the initial administration of the vaginal ring).³⁰⁹ Use a back-up method of contraception until the vaginal ring has been used continuously for 7 days.³⁰⁹

Women switching from a progestin-only contraceptive injection: Insert the vaginal ring on the same day as the next contraceptive injection would have been due.³⁰⁹ Use a back-up method of contraception until the vaginal ring has been used continuously for 7 days.³⁰⁹

Women who are switching from a progestin-only implant or a progestin-containing intrauterine device: Insert the vaginal ring on the same day as the implant or intrauterine device is removed.³⁰⁹ Use a back-up method of contraception until the vaginal ring has been used continuously for 7 days.³⁰⁹

If a woman forgets to insert a new vaginal ring at the start of any cycle, insert the ring as soon as remembered; use a back-up method of contraception until the ring has been used continuously for 7 days.³⁰⁹ If the vaginal ring is left in place for up to 1 extra week (up to 4 weeks total), remove the ring and insert a new ring after a 1-week drug-free interval.³⁰⁹ If the ring is left in place for longer than 4 weeks, rule out pregnancy and use a back-up method of contraception until a new ring has been used continuously for 7 days.³⁰⁹

Women may start using the vaginal contraceptive ring in the first 5 days following a complete first-trimester abortion; a back-up method of contraception is not needed in these women.³⁰⁹ If the contraceptive ring is not used within the first 5 days, follow the general instructions for women who did not use hormonal contraception in the preceding month.³⁰⁹

If a nonlactating woman chooses to initiate contraception postpartum with the contraceptive vaginal ring before menstruation has started, consider the possibility that ovulation and conception may have occurred prior to initiation of contraceptive therapy; use a back-up method of contraception for the first 7 days.³⁰⁹

Topical

To initiate therapy, start on the first day of the menstrual cycle or on the first Sunday after menstrual bleeding has started.³⁰⁸ Use a back-up method of contraception (condom, spermicide, diaphragm) for the first 7 days if therapy is started after day 1 of the menstrual cycle.³⁰⁸ A back-up method of contraception is not needed if the first system is applied on the first day of the menstrual cycle.³⁰⁸

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); the regimen is then repeated.³⁰⁹

Women switching from estrogen-progestin oral contraceptives: Apply the transdermal system on the first day of withdrawal bleeding.³⁰⁸ If there is no withdrawal bleeding within 5 days of the last hormonally active tablet, rule out pregnancy.³⁰⁹ If therapy with the transdermal system is initiated after the first day of bleeding, use a back-up method of contraception for 7 days.³⁰⁸ If more than 7 days elapse after receiving the last hormonally active tablet, consider the possibility of ovulation and conception.³⁰⁹

When a woman has not adhered to the prescribed transdermal contraceptive regimen by not applying the estrogen and progestin-containing system at the initiation of any cycle (i.e., day 1/first week), apply the system as soon as it is remembered and start a new dosage cycle the same day; use a back-up method of contraception for the first 7 days of the new cycle.³⁰⁸

If, in the middle of the cycle (i.e., on day 8/week 2 or day 15/week 3), the transdermal system has not been changed for 1–2 days (<48 hours), apply a new system as soon as it is remembered and continue the application schedule employed; back-up contraception is not needed.³⁰⁸ If, in the middle of the cycle the transdermal system has not been changed for more than 2 days (≥48 hours), start a new dosage cycle; use a back-up method of contraception for the first 7 days of the new cycle.³⁰⁸

When the transdermal system is not removed at the end of the application schedule (i.e., on day 22/week 4), remove the system as soon as it is remembered and continue the application schedule employed (i.e., apply system on day 28); back-up contraception is not needed.³⁰⁸

Women may start using the transdermal contraceptive system immediately after a first-trimester abortion; a back-up method of contraception is not needed.³⁰⁸ If the contraceptive preparation is not used within 5 days of a first-trimester abortion, follow instructions as if initiating transdermal contraception for the first time.³⁰⁸

Postcoital Contraception

Oral

“Yuzpe” regimen^{† [off-label]}: Take 100 mcg of ethinyl estradiol and 1 mg of norgestrel within 72 hours after unprotected intercourse, repeating the dose 12 hours later.^{254 255 257 258 259 261 262 264 265 275 282 284 345}

Other regimens^{† [off-label]}: Take 100–120 mcg of ethinyl estradiol and 1.2 mg of norgestrel or 0.5–0.6 mg of levonorgestrel within 72 hours after intercourse, repeating the dose 12 hours later.^{264 265 275 282 284 345}

If necessary, the first dose can be administered up to 120 hours after unprotected intercourse, but efficacy decreases the longer initiation of contraception is delayed.^{345 346 347}

Repeated postcoital (emergency) contraception use indicates need for counseling about other contraceptive options.^{345 350} Safety of recurrent use not established but risk appears low, even within same menstrual cycle.^{345 350} Consider possibility that risk of adverse effects may be increased with frequently repeated postcoital contraception.³⁵⁰

Dose is administered initially and then repeated 12 hours later

Contraception and Folate Supplementation

Oral

Beyaz or Safyralis used in the same dosage and administration (i.e., timing of initiation of therapy) as used in contraception.^{367 368}

Acne Vulgaris

Oral

Ortho Tri-Cyclen, Estrostep, Yaz, or Beyaz is used in the same dosage and administration (i.e., timing of initiation of therapy) as used in contraception.^a

Premenstrual Dysphoric Disorder

Oral

Yaz or Beyazis used in the same dosage and administration (i.e., timing of initiation of therapy) as used in contraception.^{366 367} (See Oral [21- or 28-day conventional-cycle preparations] under Dosage and Administration.)

Cautions for Estrogen-Progestin Combinations

Contraindications

• Hypersensitivity to the drug or any ingredient in the formulation.^a

• Known or suspected pregnancy.^a

• Undiagnosed abnormal genital bleeding.^a

• Diplopia or any ocular lesion arising from ophthalmic vascular disease.^a

• Classical migraine.^a

• Active liver disease or history of cholestatic jaundice with pregnancy or with prior use of oral contraceptives.^a

• Breast-feeding.^a

• Thrombophlebitis or thromboembolic disorders.^a

• Cerebrovascular disease or CAD (including MI).^a

• Severe hypertension.^a

• Diabetes with vascular involvement.^a

• Known or suspected carcinoma of the breast.^a

• Known or suspected estrogen-dependent neoplasia (e.g., carcinoma of the endometrium).^a

• Benign or malignant liver tumor that developed during oral contraceptive or other estrogen use.^a

• Oral contraceptives containing drospirenone: Contraindicated in women with renal impairment, hepatic tumors (benign or malignant) or hepatic disease, adrenal insufficiency, high risk of arterial or venous thrombotic diseases, undiagnosed abnormal uterine bleeding, history of breast cancer or other estrogen- or progestin-sensitive cancer, and in pregnancy.^{365 366 367 368}

• Most experts state that there currently is no real contraindication to postcoital (emergency) contraception with the recommended regimens and that the benefits generally outweigh any theoretical or proven risk.^{345 346 350}

Warnings/Precautions

Warnings

Increased risk of several serious conditions, including thromboembolism, stroke, MI, liver tumor, gallbladder disease, visual disturbances, fetal abnormalities, and hypertension.^a However, risk of serious morbidity or mortality is very small in healthy women without underlying risk factors.^a

Ethinyl Estradiol/Norelgestromin Transdermal System

Overall exposure to ethinyl estradiol and norelgestromin is higher in women receiving Ortho Evra than in women receiving an oral contraceptive preparation containing ethinyl estradiol 35 mcg and norgestimate 0.25 mg.³⁰⁸ Increased exposure to estrogen may increase the risk of certain adverse effects (e.g., venous thromboembolism).³⁰⁸ Case controlled, epidemiologic studies evaluating the risk of venous thromboembolism with Ortho Evra relative to use of oral contraceptives containing norgestimate or levonorgestrel and ethinyl estradiol 30–35 mcg reported odds ratios from 0.9 (indicating no increased risk) to 2.4 (indicating increased risk).^{308 334 351 352 353}

Continuous Regimen of Ethinyl Estradiol/Levonorgestrel

Exposure to ethinyl estradiol and levonorgestrel is higher in women receiving Lybrel than in women receiving a conventional-cycle oral contraceptive containing the same ethinyl estradiol dose and a similar dose of the progestin component; use of Lybrel results in 13 additional weeks of hormone intake per year.³³⁹

Cardiovascular and Cerebrovascular Disorders

Positive association observed between the amount of estrogen and progestin in oral contraceptives and the risk of vascular disease.^a Use smallest dosage of estrogen and progestin compatible with a low failure rate and the individual needs of the woman.^a

Use with caution in women with cardiovascular disease risk factors.^{299 301 365 366 367 368}

Increased risk of MI, mainly in women who smoke or who have risk factors for CAD (hypertension, hypercholesterolemia, obesity, diabetes, preeclamptic toxemia).^a

Women who smoke cigarettes during oral contraceptive use have an increased risk of serious adverse cardiovascular effects; risk increases with age and heavy smoking (≥15 cigarettes daily).^a (See Boxed Warning.) Women who use oral contraceptives should be strongly advised not to smoke.^a

Increases in BP may occur.^a Perform regular BP measurements prior to and during therapy.^a

Fluid retention may occur.^a Exercise caution and carefully monitor patients with conditions that might be aggravated by fluid retention.^a

Increased risk of thromboembolic and thrombotic disorders, including arterial thrombosis (e.g., stroke, MI).^{a 365 366 367 368} Risk of thrombotic events is even higher in women with other risk factors for such events.^{365 366 367 368} Known risk factors for venous thromboembolism (VTE) include smoking, obesity, family history, and other factors.^{356 365 366 367 368}

Increased risk of cerebrovascular disorders, including thrombotic and hemorrhagic stroke; risk generally is greatest in older (>35 years of age) hypertensive women who smoke.^{a 365 366 367 368} Risk of stroke also increased in women with other underlying risk factors.^{365 366 367 368}

Risk of VTE is highest during first year of oral contraceptive therapy.^{365 366 367 368 373} Some data suggest risk is highest during first 6 months of use.^{365 366 367 368} Highest VTE risk reported after initiation or resumption of therapy (after ≥4-week drug-free interval) with the same or a different oral contraceptive combination.^{365 366 367 368} Risk of thromboembolic disease gradually disappears after oral contraceptive therapy discontinued.^{365 366 367 368}

Clinicians and women should be alert to earliest possible manifestations of thromboembolic and thrombotic disorders (e.g., thrombophlebitis, pulmonary embolism, cerebrovascular insufficiency, coronary occlusion, retinal thrombosis, mesenteric thrombosis); discontinue contraceptive immediately when any of these disorders occurs or is suspected.^a

FDA safety review indicates that oral contraceptives containing drospirenone may be associated with increased risk of VTE compared with oral contraceptives containing levonorgestrel or other progestins;^{364 365 366 367 368 373} in epidemiologic studies, increase in risk with drospirenone-containing combinations ranged from no increase to threefold increase.^{357 358 359 360 361 362 365 366 367 368 369 371 372 373} Because of data limitations, causality is unclear.³⁷³ FDA will provide updates when available.³⁷³

Before initiating use of drospirenone-containing oral contraceptives in new users or in women switching from other oral contraceptives, consider risks and benefits of drospirenone-containing combinations, including VTE risk, specific to that woman.^{356 364 365 366 367 368 373} Discontinue use if arterial or venous thrombotic event occurs.^{365 366 367 368}

Discontinue estrogen-progestin contraceptive therapy, when feasible, at least 4 weeks before surgery associated with an increased risk of thromboembolism or prolonged immobilization.^{a 365 366 367 368} Wait 2 weeks after elective surgery associated with an increased risk of thromboembolism or after immobilization before resuming use.^{a 365 366 367 368}

Do not start estrogen-progestin contraceptive therapy earlier than 4 weeks after delivery in women who elect not to breast-feed or in women who have had a midtrimester pregnancy termination.^{a 365 366 367 368} Risk of thromboembolism decreases while risk of ovulation increases after first 3 weeks postpartum.^{365 366 367 368}

Carcinoma of Breast and Reproductive Organs

Many studies have shown no increased risk of breast cancer in women receiving oral contraceptives or estrogens.³¹⁸ Some studies, however, have suggested an overall increased risk of breast cancer in women receiving oral contraceptives; certain subgroups of women may be at increased risk (e.g., women <45 years of age, use early in childbearing years, use for extended periods of time, use before a first full-term pregnancy).^{223 224 225 228 229 230} These findings have occurred in only some studies and other large studies have shown no such possible associations.^{318 319 230}

Some evidence suggests that use of oral contraceptives may be associated with an increased risk of cervical carcinoma.^a

All users of estrogen-progestin contraceptives should be monitored carefully with physical examinations and Papanicolaou tests, at least annually.^a

Hepatic Effects

Benign hepatic adenomas associated with oral contraceptive use; risk appears to increase after ≥4 years of use.^a Rupture of benign hepatic adenomas may cause death through intraabdominal hemorrhage.^a

Increased risk of hepatocellular carcinoma in women using oral contraceptives for >8 years; these cancers are rare.^a

May alter liver function test results.^a If such test results are abnormal, repeat 2 months after contraceptive has been discontinued.^a Discontinue if jaundice occurs.^a

Ocular Effects

Retinal thrombosis reported.^a Discontinue contraceptive and initiate evaluation for retinal vein thrombosis immediately along with other appropriate diagnostic and therapeutic measures upon occurrence of unexplained, sudden or gradual, partial or complete loss of vision; proptosis or diplopia; papilledema; or retinal vascular lesions.^{a 365 366 367 368}

Obtain ophthalmologist assessment for contact lens wearers who develop visual disturbances or changes in lens tolerance and consider temporary or permanent cessation of contact lens wear.^a

Gallbladder Disease

Oral contraceptive use and estrogens associated with an increased lifetime relative risk of gallbladder disease/surgery, especially in young women.^{a 321} Recent studies indicate that risk may be minimal in patients using low-dose formulations.^a

Endocrine and Metabolic Effects

Decreased glucose tolerance reported.^a Monitor prediabetic and diabetic patients.^a

Increased concentrations of plasma triglyceride, low-density lipoproteins, and total phospholipids may occur.^a Closely monitor women with hyperlipidemia receiving estrogen-progestin oral contraceptives.^a

Potential exists for hyperkalemia to occur in high-risk patients (e.g., those with renal or hepatic impairment, adrenal insufficiency) receiving oral contraceptives containing drospirenone because of its antimineralocorticoid activity.^{365 366 367 368}

Headache

Discontinue contraceptive and evaluate cause if migraine occurs or is exacerbated, or when a new headache pattern develops that is recurrent, persistent, or severe.^a

Bleeding Irregularities

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.^a Evaluate for non-hormonal causes, malignancy, or pregnancy; if pathology is excluded, change to another formulation may solve the problem, or it may resolve with time.^a Rule out pregnancy in patients with amenorrhea.^a

Use of an extended-cycle oral contraceptive (e.g., LoSeasonique, Seasonale, Seasonique) results in fewer planned menses (4 per year) than a conventional-cycle oral contraceptive (13 per year) but is more often associated with bleeding irregularities.^{322 331 354}

Use of a fixed-combination, continuous-regimen (noncyclic) oral contraceptive (i.e., Lybrel) eliminates withdrawal bleeding; however, irregular bleeding and/or spotting occurs in some women.^{339 340}

Postcoital (emergency) contraception: Irregular vaginal bleeding possible; rule out pregnancy if menses is delayed >7 days after anticipated onset.³⁴⁵

General Precautions

Physical Examination and Follow-up

Annual medical history and physical examination advised.^a The physical examination may be deferred until after initiation of these contraceptives if requested by the woman and judged appropriate by the clinician.^a 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.^a Exercise particular care in women with a strong family history of breast cancer or who have breast nodules.^a

Emotional Disorders

Exercise caution in women with a history of depression; discontinue if severe depression recurs during use.^a

Specific Populations

Pregnancy

Category X.^a

Rule out pregnancy in any patient receiving conventional-cycle estrogen-progestin contraceptives who has missed 2 consecutive menstrual periods.^a Consider possibility of pregnancy after the first missed period in patients who have not adhered to the prescribed contraceptive regimen^a and in those receiving an extended-cycle estrogen-progestin contraceptive (e.g., LoSeasonique, Seasonale, Seasonique).^{322 331 354} Discontinue estrogen-progestin contraceptive use if pregnancy confirmed.^a

Current evidence does not suggest an association between inadvertent use of oral contraceptives in early pregnancy and teratogenic effects.^a In addition, extensive epidemiologic studies have revealed no increased risk of birth defects in neonates born to women who used estrogen-progestin contraceptives prior to pregnancy.^a

Estrogens and/or progestins previously used to treat threatened or habitual abortion; estrogens and/or progestins now considered ineffective for this use.^a

Progestin-only or estrogen-progestin contraceptives should not be used to induce withdrawal bleeding as a test for pregnancy.^a

Postcoital (emergency) contraception: No need to rule out pregnancy with postcoital contraceptive regimens.^{345 346 347} Postcoital contraceptive regimens (i.e., levonorgestrel, estrogen-progestins regimens) do not exhibit abortifacient properties and do not interrupt pregnancy once endometrial implantation has occurred.^{345 346 347} No known harm to pregnant woman, course of pregnancy, or fetus from postcoital contraceptive regimens.^{345 346 347 350}

Lactation

Estrogen-progestin contraceptives may decrease the quantity and quality of milk if given in the immediate postpartum period.^a Small amounts of the hormonal agents are distributed into milk and adverse effects such as jaundice and breast enlargement have been reported in infants.^a Defer the use of estrogen-progestin contraceptives, if possible, until the infant has been weaned.^a

Some clinicians recommend that lactating women receiving high-dose postcoital contraceptive regimens use alternative milk sources for their infants for at least 24 hours after completion of the regimen.²⁸⁴ Other authorities state that nursing can continue during postcoital contraceptive regimens.³⁵⁰

Pediatric Use

Safety and efficacy of estrogen-progestin contraceptives have been established in women of reproductive age.^{285 295 308 309 331 332 337 339 354 365 366 367 368} Safety and efficacy are expected to be identical for postpubertal adolescents <16 years of age and users ≥16 years of age.^{285 295 339}

Safety and efficacy of oral contraceptives containing drospirenone are expected to be the same for postpubertal adolescents <18 years of age and users ≥18 years of age.^{365 366 367 368} Not indicated before menarche.^{285 295 308 309 331 332 337 339 354 365 366 367 368}

Geriatric Use

Oral contraceptives have not been evaluated in women ≥65 years of age and are not indicated in this population.^{321 331 332 337 339 354 365 366 367 368}

Hepatic Impairment

Steroid hormones (including oral contraceptives) may be poorly metabolized in patients with hepatic dysfunction; use with caution in these individuals.^a

Common Adverse Effects

Nausea, chloasma or melasma, breakthrough bleeding and/or spotting, breast changes (tenderness, enlargement, secretion).^a

Drug Interactions

Estrogens metabolized by CYP3A4.^{295 297}

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are inhibitors, inducers, or substrates of CYP3A4 with possible alteration in metabolism of estrogen and/or other drug.^{295 297 339}

Specific Drugs

Estrogen-Progestin Combinations Pharmacokinetics

Absorption

Bioavailability

Well absorbed through skin and mucous membranes and from the GI tract.^{a 308 309 312 314 315 316 331 332 337 339}

Transdermal contraceptive system containing ethinyl estradiol and norelgestromin (Ortho Evra): Average plasma concentration and AUC_0-168 of ethinyl estradiol at steady state with Ortho Evra are 55–60% higher and peak plasma concentrations are 25% lower than with oral contraceptive preparations containing ethinyl estradiol 35 mcg; exposure to norelgestromin also is increased with Ortho Evra.³⁰⁸ Interindividual variation in plasma ethinyl estradiol concentrations is greater with Ortho Evra than with oral contraceptives.³⁰⁸

Food

Effect of food on oral bioavailability, contraceptive efficacy, and adverse GI effects of the postcoital regimens not known.^{257 278 291}

Distribution

Extent

Widely distributed.^a Distributed into bile and milk.^a

Plasma Protein Binding

Ethinyl estradiol: 98% protein bound, mainly to albumin.^a

Norethindrone: >95% protein bound to albumin and sex hormone binding globulin (SHBG).^a

Levonorgestrel: 93–98% protein bound, 34–50% to albumin, 48–65% to SHBG.²³⁸

3-Keto-desogestrel (the active metabolite of desogestrel): 96% protein bound, 64% to albumin, 32% to SHBG.²³⁸

Drospirenone: 97% protein bound, presumably to albumin.^{305 365 366 367 368}

Etonogestrel: 66% bound to albumin, 32% bound to SHBG.³⁰⁹

Norelgestromin: ≥97% bound to serum proteins (mainly albumin).³⁰⁸

Norgestimate, norelgestromin, drospirenone, and ethinyl estradiol do not appear to bind to SHBG.^{234 295 238 305 365 366 367 368}

Elimination

Metabolism

Oral contraceptive steroids are metabolized mainly in the liver and/or GI mucosa during absorption.^a

Ethinyl estradiol is mainly metabolized via aromatic hydroxylation by CYP3A4.^a Ethinyl estradiol and its metabolites undergo glucuronidation and sulfate conjugation; ethinyl estradiol undergoes extensive enterohepatic circulation as glucuronide and sulfate conjugates.^a Bacteria in the GI tract hydrolyze these conjugates, allowing reabsorption of ethinyl estradiol.^a

Mestranol is metabolized to ethinyl estradiol.^a

Levonorgestrel and norethindrone are metabolized mainly by reduction, hydroxylation, or oxidation, and by glucuronide and sulfate conjugation.^{295 296 299} Levonorgestrel and norethindrone do not undergo appreciable enterohepatic circulation.^{285 295 296}

Desogestrel is rapidly and completely metabolized by hydroxylation in the intestinal mucosa and on first pass through the liver to the active metabolite 3-keto-desogestrel.^{233 235}

Norgestimate is metabolized extensively, mainly by hydrolysis, reduction, and hydroxylation, to 17-deacetyl norgestimate, 3-keto-norgestimate, and levonorgestrel; these metabolites subsequently may undergo glucuronide and sulfate conjugation.²³⁴

Limited information is available on the pharmacokinetics of norethindrone acetate and ethynodiol diacetate; the drugs reportedly are rapidly metabolized to norethindrone.^a

Drospirenone is metabolized to 2 major inactive metabolites; one study suggests these metabolites are formed independently of the CYP enzyme system.^{305 365 366 367 368} Manufacturer states that drospirenone is metabolized only to a minor extent in vitro, mainly by CYP3A4.^{365 366 367 368}

Elimination Route

Contraceptive steroids are excreted in urine and feces, principally as metabolites and glucuronide and sulfate conjugates.^a

Half-life

Ethinyl estradiol: 6–45 hours.^{232 233 235 237 238 285 295 308 309 365 366 367 368}

Norethindrone: 5–14 hours.^{232 233 235 237 238 285 295 308 309}

Levonorgestrel: 11–45 hours.^{232 233 235 237 238 285 295 308 309}

Norelgestromin: 28 hours.^{232 233 235 237 238 285 295 308 309}

Drospirenone or etonogestrel: 30 hours.^{232 233 235 237 238 285 295 308 309 365 366 367 368}

3-Keto-desogestrel (the active metabolite of desogestrel): 12–58 hours.^{232 233 235 237 238 285 295 308 309}

Stability

Storage

Oral

Tablets

Room temperature.^a

Vaginal

Ethinyl estradiol in fixed combination with etonogestrel for vaginal administration (NuvaRing): 2–8°C until dispensed.³⁰⁹ Once dispensed, store for up to 4 months at 25°C (may be exposed to 15–30°C).³⁰⁹

Transdermal

Transdermal ethinyl estradiol in fixed combination with norelgestromin (Ortho Evra): 25°C (may be exposed to 15–30°C).³⁰⁸ After removal from the protective pouch, apply immediately.³⁰⁸

Actions

• Estrogen-progestin contraceptives elicit many of the pharmacologic responses produced by endogenous estrogens and progestins.^a

• Estrogen-progestin contraceptives produce contraceptive effects mainly by suppressing the hypothalamic-pituitary system, resulting in prevention of ovulation.^a

• The mechanism of contraceptive activity of estrogen-progestin combinations administered after intercourse (postcoital) is not known.^{254 268 285 286 287 345} Estrogen-progestin combinations in high dosage provide a short, potent burst of hormonal exposure that may effectively prevent conception by delaying or inhibiting ovulation and/or producing changes in endometrial development that are hostile to uterine implantation of the fertilized ovum, depending on when the drugs are administered relative to the menstrual cycle and the time period since intercourse.^{254 258 265 266 267 268 277 279 280 282 285 286 345} When used for postcoital contraception, high-dosage estrogen-progestin combinations are only effective before pregnancy is established; these preparations are not effective after implantation of a fertilized ovum.³⁴⁵

Advice to Patients

• Importance of avoiding cigarette smoking while taking estrogen-progestin contraceptives.^a (See Boxed Warning.)

• Importance of reading the patient information provided by the manufacturer.^a

• Importance of informing women that estrogen-progestin oral contraceptives increase risk of thrombotic and thromboembolic disorders; risk of VTE is greatest after initiation or resumption of therapy (after ≥4-week drug-free interval) with the same or a different oral contraceptive combination.^{a 365 366 367 368} Importance of discussing VTE risk with a clinician before choosing a contraceptive method (e.g., oral contraceptive).^{356 364}

• Importance of advising women that risk of VTE may be higher with drospirenone-containing oral contraceptives than with oral contraceptives containing levonorgestrel or other progestins.^{365 366 367 368} Importance of not discontinuing use of drospirenone-containing oral contraceptive without consulting clinician.^{355 356 373}

• Importance of handling the used transdermal system carefully (e.g., fold the system in half with the sticky sides together) and then discarding the system.³⁰⁸

• Importance of informing women using the Ortho Evra transdermal system that use of this preparation will result in exposure to about 60% more estrogen than use of an oral contraceptive containing 35 mcg of estrogen.³⁰⁸

• Postcoital contraception: Importance of scheduling the initial dose as conveniently as possible (but no later than 72 hours after intercourse) and of taking the second dose 12 hours after the initial dose.^{265 275 282 284 285}

• Importance of informing women that estrogen-progestin contraceptives, like all nonbarrier contraceptive methods, do not protect against human immunodeficiency virus (HIV) infection or other sexually transmitted diseases.^{285 290 365 366 367 368}

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^a

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.^a

• Importance of informing patients of other important precautionary information.^a

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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