VA Class:HS200
ATC Class:G03FA10
Etonogestrel, levonorgestrel, and norethindrone are synthetic progestin contraceptives.
Norethindrone, in small doses (minipills), is used for the prevention of conception in women who elect to use oral contraceptives as a method of contraception. Progestin-only oral contraceptives are generally reserved for women who do not tolerate estrogens or in whom estrogens are contraindicated, since progestin-only oral contraceptives are less effective than estrogen-progestin combinations and require a high level of patient compliance. When taken according to the prescribed regimen, progestin-only oral contraceptives provide almost completely effective contraception. The efficacy of oral contraceptives mainly depends on compliance with the prescribed regimen. Progestin-only oral contraceptives must be taken daily, without interruption, to be effective.
Progestin-only oral contraceptives are reported to be somewhat less effective than estrogen-progestin combinations. The pregnancy rate in women using progestin-only oral contraceptives is generally reported to be about 3 pregnancies per 100 woman-years of use. For information on the pregnancy rates reported with other methods of contraception, including estrogen-progestin combinations, see Uses in Estrogen-Progestin Combinations 68:12. Pregnancy rates are derived from various studies conducted by different investigators in different population groups and, therefore, cannot be compared precisely.
In women receiving norethindrone, the pregnancy rate, especially during the first 6 months of use, is reportedly greater in women who had not previously received oral contraceptives than in those who had been immediately switched from an estrogen-progestin combination. The reported difference in pregnancy rates probably resulted from failure to comply with the prescribed regimen. Therefore, it is especially important that women who are prescribed progestin-only oral contraceptives as initial oral contraception be advised to strictly adhere to the prescribed regimen.
For the use of norethindrone or norethindrone acetate in combination with estrogens as an oral contraceptive, see Estrogen-Progestin Combinations 68:12. For the use of the drugs in the treatment of secondary amenorrhea, endometriosis, or abnormal uterine bleeding, see Norethindrone 68:32.
Levonorgestrel-releasing intrauterine system is used for prevention of conception in women who elect to use this method of contraception.117 The manufacturer states that the system is recommended for use in women who have had one or more children; are in a stable, mutually monogamous relationship; have no history of pelvic inflammatory disease (PID); and have no history of ectopic pregnancy or any condition that would predispose to ectopic pregnancy.117 Each system may be used for up to 5 years; thereafter, the system should be removed and may be replaced with a new system if continued contraception is desired.117 The pregnancy rate in women using the levonorgestrel-releasing intrauterine system is reported as up to 0.2 pregnancies per 100 women during the first year of use; the cumulative 5-year pregnancy rate is reported to be approximately 0.7 pregnancies per 100 women.117
Etonogestrel for subcutaneous implantation (Implanon®) is used for prevention of conception in women who elect to use this method of contraception.125 The system consists of a single rod containing etonogestrel that is implanted subcutaneously in the upper arm to provide contraception for up to 3 years.125
Postcoital (Emergency) Contraception
Levonorgestrel is used as an emergency contraceptive (EC) to prevent pregnancy following unprotected intercourse or known or suspected contraceptive failure.101, 102, 106, 126, 127, 128, 129, 130, 132, 133, 136, 137 To achieve optimal efficacy, the postcoital contraceptive regimen should be initiated as soon as possible within 72 hours of unprotected intercourse.106, 132, 133, 137 Studies show that emergency contraception is moderately effective when the regimen is administered up to 120 hours after unprotected intercourse.126, 127, 128 Postcoital contraceptive efficacy diminishes as the time period between intercourse and initiation of contraception increases.101, 102, 103, 126, 127, 128
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; therefore, the progestin-only regimen generally is preferred when readily available.101, 102, 126, 127, 128, 129, 136 In a double-blind, randomized multicenter study in women who reported unprotected intercourse within 72 hours of receiving emergency contraception, a single-dose of levonorgestrel 1.5 mg was as effective in preventing pregnancy as levonorgestrel 0.75 mg every 12 hours for 2 doses.132 In a double-blind, randomized, multicenter study in women who reported only one act of unprotected intercourse within 72 hours of receiving emergency contraception, the expected pregnancy (failure) rate of 8% (with no contraception) was reduced to approximately 1% with a progestin-only regimen (levonorgestrel 0.75 mg every 12 hours for 2 doses).101, 106 In another prospective, randomized study in women who reported a single act of intercourse within 48 hours of receiving emergency contraception, failure rates with the 2-dose levonorgestrel regimen and Yuzpe regimens (levonorgestrel 0.5 mg and 0.1 mg ethinyl estradiol every 12 hours for 2 doses) were similar (2.6 versus 2.4%, respectively).102 The efficacy of treatment in both studies was greatest when the contraceptive was given during the first 24 hours after unprotected intercourse; efficacy declined during subsequent 24-hour periods.101, 102 The 2-dose levonorgestrel regimen was better tolerated than the Yuzpe regimen.101, 102 In these 2 studies, nausea occurred in 23.1 versus 50.5% and in 16.1 versus 46.5% of women receiving the 2-dose levonorgestrel regimen versus the Yuzpe regimen, respectively, while vomiting occurred in 5.6 versus 18.8% and in 2.7 versus 22.4% of women with the 2-dose levonorgestrel regimen or Yuzpe regimen, respectively.101, 102
Since unprotected intercourse that occurs outside the fertile period is unlikely to result in conception, not all women given emergency postcoital contraception are at genuine risk for pregnancy.103, 104 Therefore, a more accurate indication of the efficacy of postcoital contraceptive regimens would be based on the timing of unprotected intercourse and the probability that pregnancy would occur without treatment.102, 103, 104, 105 Analysis of data from the multicenter, progestin-only (levonorgestrel) study involving approximately 2000 women suggest that when efficacy of postcoital contraception is based on the observed versus expected number of pregnancies, the levonorgestrel-only regimen would prevent 85% of pregnancies;102 pooled analysis of observed-versus-expected pregnancy data from other studies employing the Yuzpe regimen suggest that such therapy is approximately 74% effective in preventing pregnancy.102, 103, 104, 105 However, postcoital (emergency) contraceptive regimens are not as effective as most other forms of long-term contraception.106, 126, 127, 132
Since postcoital contraceptive efficacy diminishes as the time period between intercourse and administration of the regimen increases,101, 102, 103 available data suggest that as with combination estrogen-progestin regimens, progestin-only postcoital contraception should ideally begin within 72 hours of unprotected intercourse.101, 103 Emergency contraception is moderately effective when the regimen is administered up to 120 hours after unprotected intercourse.126, 127, 128 The effectiveness of postcoital contraception administered after more than 120 hours has not been established.126, 127
The American College of Obstetricians and Gynecologists (ACOG),113, 135 other experts,111, 112, 113 and some states (e.g., Alaska, California, Hawaii, Maine, New Mexico, Washington)112 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,111, 112, 113 potentially allaying some concerns that have prompted others to advocate for restricted access. The FDA has approved the single-dose levonorgestrel regimen (Plan B One-Step®) for nonprescription (over-the-counter [OTC]) status for women of childbearing potential regardless of age.133, 134, 135, 136 Another FDA-approved product (Next Choice One Dose®) is commercially available as a single-dose levonorgestrel regimen for OTC status in women 17 years of age or older137 or as a prescription-only preparation in women younger than 17 years of age.132 A 2-dose levonorgestrel preparation is also commercially available as a prescription-only preparation for women younger than 17 years of age.106
For information on the use of combination estrogen-progestin contraceptives for postcoital contraception, see Contraception: Postcoital Contraception under Uses, in Estrogen-Progestin Combinations 68:12.
Norethindrone is administered orally once daily.119, 120 The tablets should be taken at the same time each day and continued daily without interruption, including throughout all bleeding episodes.119, 120 Women should be advised to inform a clinician if prolonged bleeding, amenorrhea, or severe abdominal pain occurs.119, 120
Levonorgestrel is administered orally or as a levonorgestrel-releasing intrauterine device.106, 117, 132, 133, 137
If vomiting occurs within 2 hours following administration of levonorgestrel (e.g., Plan B One-Step®, Next Choice One Dose®) for postcoital contraception, a clinician should be contacted to discuss the need for repeating the dose.132, 133, 137 If vomiting occurs within 2 hours following administration of the first or second dose of the levonorgestrel 2-dose regimen for emergency contraception, a clinician should be contacted to discuss the need for taking another dose.106
Levonorgestrel-releasing intrauterine system should be inserted into the uterine cavity under strict aseptic conditions following a complete review of the patient's medical and social histories, exclusion of pregnancy, and physical examination (including pelvic examination, Papanicolaou test [Pap smear], and appropriate laboratory tests for other genital diseases [e.g., gonorrhea, chlamydia] as indicated).117 Special attention should be given to determining whether the woman is at risk for ectopic pregnancy or pelvic inflammatory disease (PID).117 Patients should be reexamined shortly after the first menstrual period following insertion of the device to verify that the device is properly positioned.117 The manufacturer's labeling should be consulted for proper methods of inserting and removing the levonorgestrel-releasing intrauterine system and for associated precautions.117
Etonogestrel is administered as a nonbiodegradable implant that is inserted subcutaneously in the inner aspect of the upper arm.125 The manufacturer's labeling should be consulted for the proper method of administration and associated precautions.125
The daily dose of progestin-only oral contraceptives is 0.35 mg of norethindrone.119, 120 Therapy should begin on the first day of menstruation and should be continued each day of the year without interruption.119, 120 If therapy begins on another day, the woman should be advised to use a back-up method of contraception (e.g., condom, spermicide) for each sexual encounter during the first 48 hours.119, 120 Women who have had a miscarriage or an abortion may begin progestin-only oral contraceptives the next day.119, 120 Women who are exclusively breast-feeding their infants may begin therapy 6 weeks after delivery; women whose infants are only partially breast-fed may begin therapy with the drug 3 weeks after delivery.119, 120
If a norethindrone dose is taken more than 3 hours late or if one or more consecutive doses are missed, the last missed dose should be taken as soon as it is remembered, followed by resumption of the regular schedule; a back-up method of contraception (e.g., condom, spermicide) should be used for each sexual encounter during the next 48 hours.119, 120 If the woman is unsure of what drug regimen to take as a result of missed doses, a back-up method of contraception should be used for each sexual encounter, and one tablet should be taken each day until the clinician can be contacted.119, 120
If vomiting occurs soon after a dose, a back-up method of contraception (e.g., condom, spermicide) should be used for each sexual encounter during the next 48 hours.119, 120
If a menstrual period is delayed and norethindrone has not been taken exactly as directed, or if 45 days have elapsed since the beginning of the last menstrual period, the possibility of pregnancy should be excluded.119, 120 If pregnancy is confirmed, the woman should be advised to discontinue the progestin-only oral contraceptive.119, 120
Each levonorgestrel-releasing intrauterine system contains 52 mg of the drug and is intended to be used for periods of up to 5 years.117 When the levonorgestrel-releasing intrauterine system is used for contraception, the system is inserted into the uterine cavity within 7 days of the onset of menses.117 In postpartum women, the levonorgestrel-releasing intrauterine system should not be inserted until at least 6 weeks postpartum or until involution of the uterus is complete.117 The system may be inserted immediately after a first-trimester abortion, but insertion following a second-trimester abortion should be delayed until involution of the uterus is complete.117
The levonorgestrel-releasing intrauterine system should be removed after 5 years of use, since contraceptive efficacy beyond 5 years has not been established.117 In women who wish to continue contraception with the levonorgestrel-releasing intrauterine system, a new system may be inserted immediately following removal of the existing system.117 The system can be removed and replaced with a new system at any time during the menstrual cycle.117 For women with regular menstrual cycles who wish to initiate an alternative contraceptive method, the intrauterine system should be removed during the first 7 days of a menstrual cycle and the new method started.117 For those with irregular cycles or amenorrhea or for those in whom the system is removed after the seventh day of the menstrual cycle, the new contraceptive method should be initiated at least 7 days before removal of the intrauterine system.117
Etonogestrel implant contains 68 mg of the drug and is intended to be used for periods of up to 3 years.125
When an etonogestrel implant is used for contraception, timing of insertion depends on the patient's history.125 To initiate therapy in women who did not use hormonal contraception in the preceding month, the etonogestrel implant 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).125 When switching from other contraceptive methods, therapy with etonogestrel should be initiated in a manner that ensures continuous contraceptive coverage based on the mechanism of action of both methods (e.g., etonogestrel implant should be inserted within 7 days of the last hormonally active tablet, or removal of a transdermal patch or vaginal ring in women switching from combined estrogen-progestin contraceptives; etonogestrel implant may be inserted on any day of the month in women switching from a progestin-only oral contraceptive [without skipping any day between receiving the last progestin oral contraceptive and the initial administration of the implant]; etonogestrel implant should be inserted within the dosing period recommended for the parenteral contraceptive preparation in women switching from a progestin-only contraceptive injection; etonogestrel implant should be inserted on the same day as a progestin-containing intrauterine device is removed in women switching from this device).125 The implant may be inserted immediately after a first-trimester abortion or 21-28 days following a second-trimester abortion.125 Etonogestrel implant may be inserted 21-28 days postpartum in women who are only partially breast-feeding their infant or after the fourth postpartum week in women who are exclusively breast-feeding their infant.125 The manufacturer states that a back-up method of contraception is not needed when etonogestrel therapy is initiated according to one of these schedules.125 The implant is removed 3 years after insertion.125 In women who wish to continue contraception with etonogestrel implant, a new implant should be inserted on the same day as the existing implant is removed.125
Postcoital (Emergency) Contraception
When levonorgestrel is used alone as a short-course, progestin-only emergency postcoital contraceptive, a single 1.5-mg dose of levonorgestrel is administered as soon as possible within 72 hours of unprotected intercourse.132, 133, 137 Alternatively, a levonorgestrel dose of 0.75 mg is administered as soon as possible within 72 hours of unprotected intercourse, followed by a repeat dose of 0.75 mg 12 hours after the first dose.101, 102, 106, 126, 127, 128 Regardless of regimen, 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.126, 127, 128 Commercial preparations containing one levonorgestrel 1.5-mg tablet (e.g., Plan B® One-Step, Next Choice One Dose®) are available for this purpose.132, 133, 137 The FDA has approved Plan B® One-Step for nonprescription (over-the-counter [OTC]) status for women of childbearing potential regardless of age.133, 134, 135, 136 A commercial preparation containing 2 levonorgestrel 0.75-mg tablets also is available for postcoital contraception.106 The levonorgestrel postcoital contraceptive regimens may be used at any time during the menstrual cycle.106, 132 Since postcoital contraceptive efficacy diminishes as the time period between intercourse and administration of the regimen increases,101, 102, 103 postcoital contraception with levonorgestrel should begin as soon as possible but within 72-120 hours of unprotected intercourse.101, 103, 106, 133, 137 The effectiveness of postcoital contraception administered after more than 120 hours has not been established.126, 127
Repeated postcoital (emergency) contraception use indicates the need for counseling about other contraceptive options.126, 131 Safety of recurrent use has not been established but the risk appears to be low, even within the same menstrual cycle.126, 127 The possibility that risk of adverse effects (e.g., menstrual irregularities) may be increased with frequently repeated postcoital contraception should be considered.126
Although common adverse effects of estrogen-progestin oral contraceptives appear to be mainly caused by the estrogen, it has not been determined whether the adverse effects associated with low-dose oral progestin regimens differ from those resulting from administration of estrogen-progestin combinations. There is some evidence that the progestin component plays a major role in the development of some adverse effects of oral contraceptives when combined with estrogens. The potency and type of progestin in estrogen-progestin combinations appear to have important effects on lipoprotein lipids (high-density and low-density lipoproteins) and may contribute to the increased risk of arteriosclerotic disease in oral contraceptive users. Pending further accumulation of data on progestin-only oral contraceptives, the same precautions associated with estrogen-progestin combination therapy should be observed with progestin-only preparations. For a complete discussion of the cautions, precautions, and contraindications of oral contraceptives, see Cautions in Estrogen-Progestin Combinations 68:12.
The most frequent adverse effects of continuous oral low-dose progestin administration are menstrual irregularity, changes in menstrual flow, and/or amenorrhea, which may be difficult to differentiate from pregnancy. In clinical trials, these adverse effects caused a higher drop-out rate than that observed with estrogen-progestin oral contraceptives. Like the estrogen-progestin combination oral contraceptives, progestins can cause breakthrough bleeding, spotting, edema, weight gain, nausea, breast tenderness, headache, and mental depression; however, the incidence and severity of these adverse effects are much less with progestins than with estrogen-progestin combinations. Progestin-only oral contraceptives occasionally may alter lipid metabolism, resulting in decreased concentrations of high-density lipoprotein [HDL]-cholesterol, HDL2, apolipoprotein A-I (apo A-I), and apolipoprotein A-II (apo A-II), and increased concentrations of hepatic lipase.119, 120 There usually is no effect on concentrations of total cholesterol, HDL3, low-density lipoprotein (LDL)-cholesterol, or very low-density lipoprotein (VLDL)-cholesterol.119, 120
Adverse effects reported in 5% or more of women using the levonorgestrel-releasing intrauterine system include abdominal pain, leukorrhea, headache, vaginitis, back pain, breast pain, acne, depression, hypertension, upper respiratory infection, nausea, nervousness, dysmenorrhea, weight increase, skin disorder, decreased libido, abnormal Papanicolaou test (Pap smear), and sinusitis.117
Adverse effects reported in 5% or more of women using the etonogestrel implant include headache, vaginitis, weight increase, acne, breast pain, upper respiratory infection, abdominal pain, pharyngitis, leukorrhea, influenza-like symptoms, dizziness, dysmenorrhea, back pain, emotional lability, nausea, pain, nervousness, sinusitis, depression, and insertion site pain.125
Limited data from 2 comparative studies in which women receiving emergency postcoital contraception with either an estrogen-progestin regimen (levonorgestrel 0.5 mg and 100 mcg ethinyl estradiol every 12 hours for 2 doses) or a progestin-only regimen (levonorgestrel 0.75 mg every 12 hours for 2 doses) indicate a lower incidence of nausea or vomiting with the progestin-only (levonorgestrel) regimen.101, 102 In these 2 studies, nausea occurred in 23.1 versus 50.5% and in 16.1 versus 46.5% of women receiving the 2-dose levonorgestrel regimen versus the estrogen-progestin regimen, respectively, while vomiting occurred in 5.6 versus 18.8% and in 2.7 versus 22.4% of women with the levonorgestrel- or estrogen-progestin regimen, respectively.101, 102 Other adverse effects occurring in one of these studies with the 2-dose levonorgestrel regimen included nausea (23% of patients), abdominal pain (17.6% of patients), fatigue (16.9% of patients), headache (16.8% of patients), heavier or lighter menstrual bleeding (13.8 or 12.5% of patients, respectively), dizziness (11.2% of patients), breast tenderness (10.7% of patients), vomiting (5.6% of patients), or diarrhea (5% of patients).106 Adverse effects reported with the single-dose levonorgestrel regimen include heavier menstrual bleeding (30.9% of patients), nausea (13.7% of patients), lower abdominal pain (13.3% of patients), fatigue (13.3% of patients), headache (10.3% of patients), dizziness (9.6% of patients), breast tenderness (8.2% of patients), or more than a 7-day delay in menses (4.5% of patients).132 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).111, 112, 113
Other adverse reactions which have been reported in women receiving progestins are weight gain or loss, changes in cervical erosion and secretions, cholestatic jaundice, allergic rash with or without pruritus, melasma or chloasma, breast changes (tenderness, enlargement, and secretion), and hirsutism.
Precautions and Contraindications
It is good medical practice that all women, including those receiving progestin-only oral contraceptives, have a complete medical history and physical examination performed periodically (e.g., annually);119, 120 the physical examination may be deferred until after initiation of therapy if requested by the woman and judged appropriate by the clinician.119, 120 Physical examination is not required prior to initiating therapy with oral levonorgestrel for postcoital (emergency) contraception.106, 126, 132 In women receiving the levonorgestrel-releasing intrauterine system, complete medical and social histories (including those of the partner) and physical examination (including pelvic examination, Papanicolaou test [Pap smear], and appropriate laboratory tests for other genital diseases [e.g., gonorrhea, chlamydia] as indicated) should be performed, and pregnancy should be excluded prior to insertion of the intrauterine system; special attention should be given to determining whether the woman is at risk for ectopic pregnancy or pelvic inflammatory disease (PID).117
Safety and efficacy of progestin contraceptives have been established in women of reproductive age.106, 117, 119, 120, 125, 132 Safety and efficacy of long-term progestin contraceptives are expected to be identical for postpubertal adolescents younger than 16 years of age and women 16 years of age or older.119, 120, 125, 128 Safety and efficacy of progestin emergency contraceptives are expected to be identical for postpubertal adolescents younger than 17 years of age and women 17 years of age or older.106, 132 Progestin contraceptives are not indicated before menarche.106, 117, 119, 120, 125, 132
Progestin contraceptives have not been evaluated in women older than 65 years of age and these drugs are not indicated for use in postmenopausal women.106, 117, 125, 132
Slight deterioration in glucose tolerance, coupled with increases in plasma insulin concentrations, may occur in some patients receiving progestin-only contraceptives.119, 120 However, in women with diabetes mellitus receiving progestin-only contraceptives, insulin requirements generally are unchanged.119, 120 Nevertheless, prediabetic or diabetic women should be carefully monitored while receiving these contraceptives.117, 118, 119, 120
Headache, including migraine headache, has been reported during progestin-only contraceptive therapy.117, 119, 120 Progestin-only oral contraceptives should be discontinued and the cause evaluated when migraine occurs or is exacerbated, or when severe, persistent, or recurrent headache develops.119, 120
Because the presence of organisms capable of causing PID cannot be determined by appearance, and because insertion of an intrauterine system may be associated with introduction of vaginal bacteria into the uterus, the levonorgestrel-releasing intrauterine system should be inserted under strict aseptic conditions.117 Administration of anti-infectives may be considered; however, the benefit of such prophylactic measure is unknown.117 Syncope, bradycardia, or other neurovascular episodes may occur during insertion or removal of the intrauterine system, particularly in women predisposed to these conditions or in those with cervical stenosis.117 If decreased pulse, perspiration, or pallor is observed, the woman should remain supine until these signs have disappeared.117 Women receiving the levonorgestrel-releasing intrauterine system who have certain types of valvular or congenital heart disease and surgically constructed systemic-pulmonary shunts are at increased risk of infective endocarditis and, possibly, septic embolism.117 Women with known congenital heart disease who may be at increased risk should receive appropriate anti-infectives at the time of insertion and removal of the intrauterine system.117 Women requiring chronic corticosteroid therapy or insulin for diabetes mellitus should be carefully monitored for development of infection.117 The levonorgestrel-releasing intrauterine system should be used with caution in women who have a coagulopathy or are receiving anticoagulants.117 Use of the intrauterine system in women with vaginitis or cervicitis should be postponed until appropriate treatment has eradicated the infection and until it has been determined that the cervicitis is not caused by Neisseria gonorrhoeae or Chlamydia .117
Because the levonorgestrel-releasing intrauterine system may be displaced following insertion, women should be reexamined and evaluated shortly after the first postinsertion menses, but definitely within 3 months after insertion.117 During examination, the removal threads of the intrauterine system should be located; if the threads are not visible, location of the system should be verified (e.g., by radiograph or ultrasound, by gentle exploration of the uterine cavity with a probe).117 If the intrauterine system is in place with no evidence of perforation, no intervention is indicated.117 If the system is verified as displaced, it should be removed, and a new system may be inserted at that time or during the next menses if it is certain that conception has not occurred.117 If expulsion has occurred, the system may be replaced within 7 days of a menstrual period after pregnancy has been excluded.117 Partial or complete expulsion of any intrauterine system may result in bleeding or pain; however, expulsion may occur without the woman's knowledge.117
Concomitant use of progestin-only contraceptives with drugs that induce hepatic microsomal enzymes (e.g., barbiturates, carbamazepine, phenytoin, HIV protease inhibitors, rifampin, St. John's wort [ Hypericum perforatum ]) reduces contraceptive efficacy, possibly resulting in unintended pregnancy or breakthrough bleeding.117, 119, 120 Effects of hepatic enzyme inducers on the contraceptive efficacy of the levonorgestrel-releasing intrauterine system have not been evaluated.117 No significant interaction has been found when progestin-only oral contraceptives are used concomitantly with broad-spectrum anti-infectives.119
Women should be informed that progestin-only contraceptives do not protect against human immunodeficiency virus (HIV) infection or other sexually transmitted diseases.106, 117, 119, 120, 125, 132, 133, 137
Levonorgestrel 0.75 or 1.5 mg used for postcoital (emergency) contraception is not effective in terminating an existing pregnancy.106, 132, 133, 137 Rapid return of fertility is likely following use of levonorgestrel for postcoital contraception.106, 132 Routine methods of contraception should be continued or initiated as soon as possible following use of levonorgestrel to ensure ongoing pregnancy prevention.106, 132
Women receiving progestin-only oral contraceptives should be advised to take the tablets exactly as directed and at the same time every day, including throughout all bleeding episodes.119, 120 (See Dosage and Administration.) Women should be advised to inform a clinician if prolonged bleeding, amenorrhea, or severe abdominal pain occurs.119, 120 Although progestin-only oral contraceptives do not affect the quality or quantity of breast milk in lactating women,119, 120 isolated cases of decreased milk production have been reported, and lactating women are advised to contact a clinician if they are not producing enough milk.120 The World Health Organization states that nursing women can continue to breast-feed without restriction during postcoital (emergency) contraceptive regimens.131
Women considering use of the levonorgestrel-releasing intrauterine system should be encouraged to review the manufacturer's patient information and to discuss with a clinician the risks and benefits associated with the use of an intrauterine contraceptive system.117 Following insertion of the intrauterine system, women should be instructed on how to check after their menstrual period to ensure that the removal threads still protrude from the cervix and should be cautioned not to pull on the threads and displace the system.117
Irregular menstrual patterns are common in women receiving progestin-only contraceptives.117, 119, 125 If genital bleeding patterns are suggestive of infection, malignancy, or other pathologic causes, such causes should be ruled out.119, 120 If prolonged amenorrhea develops in women receiving progestin-only oral contraceptives, the possibility of pregnancy should be evaluated.119, 120 In women using the levonorgestrel-releasing intrauterine system, the number of days of bleeding and spotting may be increased and bleeding patterns may be irregular during the first 3-6 months of use; thereafter, bleeding may remain irregular but the number of days with bleeding or spotting is decreased.117 If bleeding irregularities develop during prolonged use of the levonorgestrel-releasing intrauterine system, pathologic causes should be ruled out.117 Amenorrhea develops within 1 year in about 20% of women using the levonorgestrel-releasing intrauterine system.117 The possibility of pregnancy should be considered in women using this contraceptive method if menstruation does not occur within 6 weeks of the onset of the previous menstrual period.117 Once pregnancy has been excluded, repeated pregnancy tests are not required in women using the levonorgestrel-releasing intrauterine system in the absence of other evidence of pregnancy or unless pelvic pain is present.117
Delayed atresia of ovarian follicles, with resulting follicular enlargement, may occur in patients receiving progestins.119, 120 Follicular enlargement generally is asymptomatic or associated with mild abdominal pain and resolves spontaneously; in rare cases, surgery may be required.119, 120
The rate of ectopic pregnancy in women receiving progestin-only oral contraceptives has been reported as 5 ectopic pregnancies per 1000 woman-years of use.119, 120 Up to 10% of pregnancies reported in clinical trials in women receiving progestin-only oral contraceptives have been ectopic.106, 119, 120, 132 The possibility of ectopic pregnancy should be considered whenever a patient receiving a low-dose progestin oral contraceptive becomes pregnant or experiences severe lower abdominal pain.106, 119, 120, 132, 133, 137 A follow-up physical or pelvic examination is recommended by the manufacturers if there is any question regarding the general health or pregnancy status of a woman following administration of levonorgestrel 0.75 or 1.5 mg for postcoital (emergency) contraception.106, 132 The manufacturers state that a history of ectopic pregnancy does not need to be considered a contraindication to progestin-only oral contraceptives.106, 119, 120, 131, 132
The rate of ectopic pregnancy in clinical trials in women using the levonorgestrel-releasing intrauterine system has been reported to be 1 ectopic pregnancy per 1000 woman-years of use, a rate not substantially different from that in sexually active women not using any contraceptive method.117 About one-half of the pregnancies reported during these clinical trials were ectopic.117 Patients with a history of ectopic pregnancy were excluded from clinical trials of the levonorgestrel-releasing intrauterine system, and use of this contraceptive method is not recommended in women with a history of ectopic pregnancy or conditions that may predispose to ectopic pregnancy.117 Women using the levonorgestrel-releasing intrauterine system should be taught to recognize and report symptoms of ectopic pregnancy.117
In women who have intrauterine pregnancies while using an intrauterine contraceptive device, septic abortion (resulting in septicemia, septic shock, and death) can occur.117 If pregnancy occurs in a woman using the levonorgestrel-releasing intrauterine system, the intrauterine system should be removed.117 Removal or manipulation of the system may result in pregnancy loss.117 If the system cannot be removed or if the woman chooses not to have the system removed, she should be advised that failure to remove the system increases the risk of miscarriage, sepsis, and premature labor and delivery, and she should be followed closely and advised to report immediately any flu-like symptoms, fever, chills, cramping, pain, bleeding, vaginal discharge, or leakage of fluid.117 The long-term effects on the fetus of leaving the levonorgestrel-releasing system in place as the pregnancy progresses are unknown.117 Clinical experience with pregnancy outcomes in such cases is limited, and the possibility of teratogenic effects cannot be completely excluded.117 Congenital anomalies have been reported infrequently when the levonorgestrel-releasing system was not removed; however, the role of the levonorgestrel-releasing system in the development of these anomalies has not been established.117
Group A streptococcal sepsis has been reported rarely following insertion of the levonorgestrel-releasing intrauterine system.117 Severe pain has occurred within hours of insertion, followed by onset of sepsis within several days.117 Use of strict aseptic technique during insertion of the device is essential.117
Use of intrauterine contraceptive devices is associated with an increased risk of PID, with the highest risk occurring shortly (generally within 20 days) after insertion of the device.117 The decision to use the levonorgestrel-releasing intrauterine system should include consideration of the risk of PID.117 If the woman or her partner has multiple sexual partners, risk of PID is increased and the levonorgestrel-releasing intrauterine system should not be used.117 Risk also is increased in women with a history of PID, and use of the device is contraindicated in such women unless there has been a subsequent intrauterine pregnancy.117 All women who are considering use of the levonorgestrel-releasing intrauterine system should be informed of the possibility of PID and long-term sequelae (tubal damage resulting in ectopic pregnancy or infertility or, less often, hysterectomy or death) and should be taught to recognize signs and symptoms of PID (e.g., prolonged or heavy bleeding, unusual vaginal discharge, abdominal or pelvic pain or tenderness, dyspareunia, chills, fever).117 PID may be asymptomatic but still result in tubal damage and long-term sequelae.117 If PID is suspected or confirmed, the patient should be promptly evaluated and appropriate treatment initiated.117
Actinomycosis also has been reported in association with intrauterine contraceptive devices.117 If symptomatic actinomycosis occurs, the intrauterine system should be removed and appropriate anti-infective treatment initiated.117 Management of asymptomatic patients is controversial.117
Partial penetration or embedment of the levonorgestrel-releasing intrauterine system in the myometrium may decrease contraceptive efficacy and make removal of the device difficult.117 If perforation of the uterus or cervix occurs, the device must be removed and surgery may be required.117 Potential complications include adhesions, peritonitis, intestinal perforation or obstruction, abscesses, and erosion of adjacent viscera.117 The risk of perforation is increased in lactating women.117 To decrease the risk of perforation in postpartum women and in women who have undergone a second-trimester abortion, insertion of the device should be delayed until uterine involution is complete.117
The levonorgestrel-releasing intrauterine system should be removed if any of the following occur: menorrhagia and/or metrorrhagia producing anemia, HIV infection, sexually transmitted disease, pelvic infection, endometritis, symptomatic genital actinomycosis, intractable pelvic pain, severe dyspareunia, pregnancy, endometrial or cervical malignancy, or uterine or cervical perforation.117 Removal of the intrauterine system also should be considered if any of the following conditions arise for the first time: migraine, focal migraine with asymmetrical visual loss or other manifestations indicating transient cerebral ischemia, exceptionally severe headache, jaundice, marked increase of blood pressure, or severe arterial disease (e.g., stroke, myocardial infarction).117
The manufacturers state that progestin-only oral 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, active liver disease, benign or malignant liver tumor, or known or suspected carcinoma of the breast.119, 120, 125 In addition to the usual contraindications associated with oral progestin therapy, the levonorgestrel-releasing intrauterine system is contraindicated in patients with congenital or acquired uterine anomalies (including fibroids) if they distort the uterine cavity, acute PID or a history of PID unless there has been a subsequent intrauterine pregnancy, postpartum endometritis or infected abortion in the previous 3 months, known or suspected uterine or cervical neoplasia or an unresolved abnormal Papanicolaou test (Pap smear) result, untreated acute cervicitis or vaginitis (including bacterial vaginosis or other lower genital tract infection until the infection is controlled), conditions associated with increased susceptibility to infection (e.g., leukemia, acquired immunodeficiency syndrome [AIDS], IV drug abuse), genital actinomycosis, or a history of ectopic pregnancy or any condition that would predispose to ectopic pregnancy.117 The levonorgestrel-releasing intrauterine system also is contraindicated if a previously inserted intrauterine contraceptive device has not been removed or if the woman or her partner has multiple sexual partners.117
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.126, 127, 131 Levonorgestrel for emergency contraception should not be used as a woman's routine form of contraception.106, 132, 133, 137 In addition, use of levonorgestrel for emergency contraception is not recommended in women who are hypersensitive to the drug or any ingredient in the formulation or in those with known or suspected pregnancy.106, 132, 133, 137
For information on drug interactions associated with oral contraceptives, see Drug Interactions in Estrogen-Progestin Combinations 68:12.
For information on laboratory test interferences associated with oral contraceptives, see Laboratory Test Interferences in Estrogen-Progestin Combinations 68:12.
Norethindrone shares the actions of progestins. Although the exact mechanism of action of progestin-only oral contraceptives is not known, norethindrone, when administered in usual contraceptive doses, appears to act principally by altering cervical mucus so that sperm migration into the uterus is inhibited. Progestational changes in the endometrium also occur which may inhibit implantation of the fertilized ovum in the uterus. In addition, continuous administration of low doses of norethindrone alters the rate of ovum transport by changing motility and secretion in fallopian tubes. Norethindrone prevents pregnancy even in the presence of ovulation. Norethindrone suppresses ovulation and causes ovarian and endometrial atrophy at high doses; the drug does not consistently suppress ovulation when administered in a continuous low-dose regimen. In low doses, norethindrone causes variable suppression of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Norethindrone has mild androgenic activity. At low doses, norethindrone also has some estrogenic activity.
The precise mechanism of contraceptive activity of levonorgestrel administered after intercourse (postcoital) is not known.126 Levonorgestrel has been shown to inhibit or delay ovulation or fertilization; other mechanisms of action for preventing pregnancy presumably are involved.106, 126 Levonorgestrel is only effective before pregnancy is established.106, 126, 132 Once implantation occurs, levonorgestrel is ineffective in preventing pregnancy.106, 126, 132
For a discussion on the absorption, distribution, and elimination of oral contraceptive steroids, including norethindrone, see Pharmacokinetics in Estrogen-Progestin Combinations 68:12.
Following insertion of an intrauterine system containing 52 mg of levonorgestrel (Mirena®), the drug is initially released into the uterine cavity at a rate of 20 mcg per day.117 The rate of drug release decreases progressively to about one-half of the initial rate after 5 years of use.117 Plasma levonorgestrel concentrations stabilize at 150-200 pg/mL a few weeks following insertion of the system; concentrations at 12, 24, and 60 months following insertion of the device reportedly average 180, 192, and 159 pg/mL, respectively.117
Following subcutaneous insertion of etonogestrel implant, the drug is released at a rate of 60-70 mcg per day at week 5-6; the rate decreases to 35-45 mcg per day at the end of the first year, to 30-40 mcg per day at the end of the second year, and then to 25-30 mcg per day at the end of the third year.125 Plasma etonogestrel concentrations of 781-894 pg/mL are achieved within a few weeks following insertion of the implant; concentrations at 12, 24, and 36 months following insertion of the device reportedly average 192-261, 154-194, and 156-177 pg/mL, respectively.125
Following oral administration of a single 0.75- or 1.5-mg dose of levonorgestrel, the drug is rapidly and completely absorbed with peak plasma concentrations of 14 or 19 ng/mL achieved in 1.6 or 1.7 hours, respectively.106, 132
Etonogestrel, levonorgestrel, and norethindrone are synthetic progestins which are used as contraceptives. Norethindrone occurs as a white to creamy white, crystalline powder and is practically insoluble in water and sparingly soluble in alcohol.
The commercially available levonorgestrel-releasing intrauterine system consists of a T-shaped polyethylene frame with a cylindrical drug reservoir around the vertical stem.117 The drug reservoir, a mixture of levonorgestrel and silicone, contains 52 mg of levonorgestrel and is covered by a silicone membrane.117 The polyethylene frame contains barium sulfate and is radiopaque.117 A monofilament polyethylene removal thread is attached to a loop at the end of the vertical stem of the frame.117
Etonogestrel is commercially available as a nonbiodegradable implant.125 The implant is 4 cm long and has a diameter of 2 mm.125 The implant does not contain latex and is not radiopaque.125
Norethindrone tablets should be stored at a temperature of 25°C but may be exposed to temperatures ranging from 15-30°C.119 Commercially available oral contraceptives are provided in mnemonic dispensing packages which are exempted from the child safety packaging requirements of the US Poison Prevention Packaging Act. Levonorgestrel tablets should be stored at 20-25°C.106, 132, 133, 137
The levonorgestrel-releasing intrauterine system should be stored at a temperature of 25°C but may be exposed to temperatures ranging from 15-30°C.117 The system is supplied as a sterile device and should not be resterilized.117 The device should not be used if the inner package is damaged or has been opened.117
Etonogestrel implant should be stored at a temperature of 25°C but may be exposed to temperatures ranging from 15-30°C.125
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
FDA has approved Next Choice One Dose® for nonprescription (over-the-counter [OTC]) status for women 17 years of age or older;137 the contraceptive will remain a prescription-only preparation for women younger than 17 years of age.132
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Intrauterine | Intrauterine System | 52 mg | ||
Oral | Tablets | 0.75 mg* | Levonorgestrel Tablets (available in pack of 2 tablets) | |
1.5 mg* | ||||
Levonorgestrel Tablets | ||||
Next Choice One Dose® | ||||
Opcicon® One-Step | ||||
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 0.35 mg | ||
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions April 1, 2016. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
101. Ho PC, Kwan MSW. A prospective randomized comparison of levonorgestrel with the Yuzpe regimen in post-coital contraception. Hum Reprod . 1993; 8:389-92. [PubMed 8473453]
102. Task Force on Postovulatory methods of Fertility Regulation. Randomized controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. Lancet . 1998; 352:428-33. [PubMed 9708750]
103. Glasierg A. Emergency postcoital contraception. N Engl J Med. 1997;337:1058-64. [PubMed 9321535]
104. Ellertson C. History and efficacy of emergency contraception: beyond Coca-Cola. Fam Plann Perspect . 1996; 28:44-8. [PubMed 8777937]
105. Trussell J, Ellertson C, Stewart F. The effectiveness of the Yuzpe regimen of emergency contraception. Fam Plann Perspect . 1996; 28:58-64,87,88. [PubMed 8777940]
106. Perrigo. Levonorgestrel tablets 0.75 mg prescribing information. Allegan, MI; 2009 Aug.
107. Wyeth Laboratories. Levonorgestrel implants (Norplant® system) prescribing information. Philadelphia, PA; 2001 Oct 12.
108. deVane PJ. Dear Norplant® provider letter. Philadelphia, PA: Wyeth-Ayerst Pharmaceuticals; 2000 Aug 10.
109. deVane PJ. Dear health care provider letter: Important Norplant® system (levonorgestrel implants) update. Philadelphia, PA: Wyeth-Ayerst Pharmaceuticals; 2000 Sep 13.
110. Kusiak V. Dear health care provider letter: Important Norplant® system (levonorgestrel implants) update: Back-up contraception no longer required on specified lots. Philadelphia, PA: Wyeth Pharmaceuticals; 2002 Jul 26.
111. Raine TR, Harper CC, Rocca CH et al. Direct access to emergency contraception through pharmacies and effect on unintended pregnancy and STIs: a randomized controlled trial. JAMA . 2005; 293:54-62. [PubMed 15632336]
112. Litt IF. Placing emergency contraception in the hands of women. JAMA . 2005; 293:98-9. [PubMed 15632343]
113. American College of Obstetricians and Gynecologists. Statement of Vivian M. Dickerson, MD, President on JAMA emergency study. 2005 Jan 5. Press release.
114. Wyeth. Norplant® System (levonorgestrel implants) prescribing information. Philadelphia, PA: 2005 May.
115. FDA Statement. FDA takes action on Plan B: statement by FDA commissioner Lester M. Crawford. 2005 Aug 26. From FDA website. [Web]
116. FDA. FDA's decision regarding Plan B: questions and answers. 2004 May 7. From FDA web site. [Web]
117. Berlex. Mirena® (levonorgestrel-releasing intrauterine system) prescribing information. Montville, NJ; 2006 Apr.
118. Wyeth. Ovrette® (norgestrel) tablets prescribing information. Philadelphia, PA; 2003 Oct.
119. Ortho-McNeil Pharmaceutical, Inc. Ortho Micronor® (norethindrone) tablets prescribing information. Raritan, NJ; 2005 Oct.
120. Watson Pharma. Nor-QD® (norethindrone 0.35 mg tablets, USP) prescribing information. Corona, CA; 2006 Mar.
121. FDA News. FDA approves over-the-counter access for plan B for women 18 and older prescription remains required for those 17 and under. 2006 Aug 24. From FDA website. [Web]
122. Steven Galson, Director, Center for Drug Evaluation and Research. Plan B®; approval letter. 2006 Aug 24. From FDA website. [Web]
123. Andrew C. Von Eschenbach, Acting commissioner, United States Food and Drug Administration. Appropriate age restriction for Plan B®. 2006 Aug 23. From FDA website. [Web]
124. Barr Pharmaceuticals. FDA grants OTC status to Barr's plan B(R) emergency contraceptive. From Barr website. Accessed 28 Aug 2006. [Web]
125. Organon. Implanon® (etonogestrel) implant prescribing information. Roseland, NJ; 2006 Jul.
126. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 112: Emergency contraception. Obstet Gynecol . 2010; 115:1100-9. [PubMed 20410799]
127. American Academy of Pediatrics Committee On Adolescence. Emergency contraception. Pediatrics . 2012; 130:1174-82. [PubMed 23184108]
128. American Academy of Pediatrics Committee on Adolescence. Policy statement: contraception and adolescents. Pediatrics . 2007; 120:1135-48. [PubMed 17974753]
129. Cheng L, Che Y, Gülmezoglu AM. Interventions for emergency contraception. Cochrane Database Syst Rev . 2012; 8:CD001324.
130. Polis CB, Grimes DA, Schaffer K, et al for the Cochrane Collaboration. Advance provision of emergency contraception for pregnancy prevention (review). Cochrane Database of Syst Rev . 2010; 3: CD005497.
131. World Health Organization. Department of Reproductive Health and Research. Medical eligibility criteria for contraceptive use. 5th ed. Geneva, Switzerland: World Health Organization; 2015. [Web]
132. . Actavis. Next Choice One Dose® (levonorgestrel) tablet 1.5 mg prescribing information. Parsippany, NJ. 2012 Oct.
133. Teva Women's Health. Plan B One-Step® (levonorgestrel) tablet product information. North Wales, PA. 2011 Dec. Accessed 2015 Nov 12. [Web]
134. FDA news release. FDA approves Plan B One-Step emergency contraceptive for use without a prescription for all women of child-bearing potential. 2013 Jun 20. From FDA website. Accessed 2015 Nov 12. [Web]
135. American Academy of Pediatrics (AAP), American Congress of Obstetricians and Gynecologists (ACOG), and Society for Adolescent Health and Medicine (SAHM) joint statement. Medical groups praise justice department decision increasing access to emergency contraception. 2013 Jun 11. From ACOG website. Accessed 2015 Nov 12. [Web]
136. American Academy of Pediatrics Committee on Adolescence. Contraception for adolescents. Pediatrics . 2014; 134:e1244-56.
137. Actavis. Next Choice One Dose® (levonorgestrel) tablet 1.5 mg product information. Parsippany, NJ. 2014 Mar.