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Progestins

Class: Contraceptives
ATC Class: G03FA10
VA Class: HS200
CAS Number: 54048-10-1
Brands: Fallback Solo, Implanon, Micronor, Mirena, Next Choice One Dose, Nor-QD, Opcicon One-Step, Plan B One-Step

Introduction

Contraceptives containing synthetic progestinic steroids.

Uses for Progestins

Contraception

Prevention of conception in women.

Predominantly used by women who are breastfeeding and in those who do not tolerate estrogens or in whom estrogens are contraindicated.

Levonorgestrel-releasing intrauterine system (Mirena): Intended for women who have had ≥1 child; 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.

Postcoital (Emergency) Contraception

Prevention of conception after unprotected intercourse (including known or suspected contraceptive failure) as an emergency contraceptive (“morning-after” pills). Postcoital (emergency) contraceptive regimens are not as effective as most other forms of long-term contraception; do not use as routine forms of contraception.

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; levonorgestrel generally preferred when readily available.

Progestins Dosage and Administration

Administration

Administer norethindrone orally.

Administer levonorgestrel orally or as an intrauterine system.

Administer etonogestrel implant by sub-Q insertion.

Oral Administration

Contraception

Take as near as possible to the same time each day (i.e., at regular 24-hour intervals) and continue daily without interruption to ensure maximum contraceptive efficacy.

If vomiting occurs soon after a dose, use a back-up method of contraception (e.g., condoms, foam, sponges) for 48 hours.

Available in a mnemonic dispensing package designed to aid the user in complying with the prescribed dosing regimen.

Postcoital (Emergency) Contraception

Plan B One-Step, Next Choice One Dose: Administer as soon as possible but preferably within 72 hours following unprotected sex.

Levonorgestrel 2-dose regimen: Administer the first dose as soon as possible within 72 hours of unprotected sex followed by a second dose 12 hours after the first dose.

Most data support administration of either regimen up to 120 hours after unprotected intercourse if necessary, but efficacy decreases as initiation of contraception becomes more remote from unprotected intercourse.

May be used at any time during the menstrual cycle. Efficacy not established if administered >120 hours after unprotected sex.

Plan B One-Step, Next Choice One Dose : If vomiting occurs within 2 hours after administration, contact clinician to discuss repeating the dose.

Levonorgestrel 2-dose regimen: If vomiting occurs within 2 hours after administration of either the first or second dose, contact clinician to discuss taking another dose.

Food not effective in reducing adverse GI effects (i.e., nausea).

Sub-Q Administration

Insert etonogestrel implant (Implanon) subdermally in the inner aspect of the upper arm about 6–8 cm above the elbow crease. Consult manufacturer’s labeling for proper method of administration and associated precautions.

Intrauterine Administration

Insert levonorgestrel-releasing intrauterine system (Mirena) into the uterine cavity under strict aseptic conditions. (See Intrauterine Device Considerations under Cautions.) Consult manufacturer’s labeling for proper methods of inserting and removing the intrauterine system and for associated precautions.

Dosage

When switching contraceptive methods, initiate new therapy in a manner that ensures continuous contraceptive coverage based on the mechanism of action of both methods.

Adults

Contraception
Oral

Norethindrone: 0.35 mg daily. Take 1 tablet each day and continue daily without interruption. Start on the first day of the menstrual cycle. If the first dose is taken on another day, use back-up method of contraception (e.g., condom, spermicide) for each sexual encounter for the next 48 hours.

Women switching from estrogen-progestin oral contraceptives: Start norethindrone on the day after the last hormonally active tablet.

Women may start using norethindrone tablets on the next day after a miscarriage or an abortion.

Women whose infants are only partially breast-fed may begin norethindrone 3 weeks after delivery. Women who are exclusively breast-feeding their infants may begin 6 weeks after delivery.

When a dose is taken >3 hours late or if one or more consecutive doses are missed, take the missed dose as soon as remembered, then resume regular schedule; use a back-up method of contraception (e.g., condom, spermicide) for 48 hours. 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 one tablet daily until clinician contacted.

Sub-Q

Etonogestrel contraceptive implant (Implanon): One 68-mg implant every 3 years.

To initiate therapy in women who did not use hormonal contraception in the preceding month, insert the contraceptive implant on or before day 5 of the cycle; a back-up method of contraception is not needed.

Women switching from estrogen-progestin oral contraceptives, contraceptive transdermal system, or vaginal contraceptive ring: Insert the contraceptive implant within 7 days of the last hormonally active tablet, removal of a transdermal patch, or removal of the vaginal ring; a back-up method of contraception is not needed.

Women switching from progestin-only oral contraceptives: Insert the contraceptive implant on any day of the month (without skipping any day between receiving the last progestin oral contraceptive and the initial administration of the implant); a back-up method of contraception is not needed.

Women switching from a progestin-only contraceptive injection: Insert the contraceptive implant on the same day as the next contraceptive injection would have been due; a back-up method of contraception is not needed.

Women switching from a progestin-containing intrauterine device: Insert the contraceptive implant on the same day as the intrauterine device is removed; a back-up method of contraception is not needed.

The contraceptive implant can be inserted immediately after a first-trimester abortion. If therapy with the contraceptive insert is not initiated within 5 days of a first-trimester abortion, follow the instructions for women who did not use hormonal contraception in the preceding month.

The contraceptive implant can be inserted 21–28 days after a second-trimester abortion.

The contraceptive implant can be inserted 21–28 days postpartum in women who are not exclusively breast-feeding; a back-up method of contraception is not needed. The implant can be inserted after the fourth postpartum week in women who are exclusively breast-feeding their infant. If implant insertion occurs >4 weeks postpartum, use back-up method of contraception for 7 days.

Remove implant 3 years after insertion. At time of implant removal, may insert another implant to continue therapy.

Intrauterine

Levonorgestrel-releasing intrauterine contraceptive system (Mirena): One system containing 52 mg every 5 years.

To initiate therapy, insert the intrauterine contraceptive system within 7 days of menses onset.

The intrauterine contraceptive system can be inserted immediately after a first-trimester abortion; delay insertion until involution of the uterus is complete after a second-trimester abortion.

Do not insert the intrauterine contraceptive system until 6 weeks postpartum or after involution of the uterus is complete.

Remove the intrauterine contraceptive system after 5 years of use (contraceptive efficacy >5 years not established). At time of system removal, may insert another intrauterine contraceptive system to continue therapy; removal and replacement with a new system can be done at any time during the menstrual cycle.

For women with regular menstrual cycles who wish to initiate an alternative contraceptive method, remove the intrauterine system during the first 7 days of a menstrual cycle and start new method. For those with irregular cycles or amenorrhea or for those in whom the system is removed after the seventh day of the menstrual cycle, initiate the new contraceptive method at least 7 days before removal of the intrauterine system.

Postcoital (Emergency) Contraception
Oral

Levonorgestrel one-dose regimen (e.g., Plan B One-Step, Next Choice One Dose): Single 1.5-mg dose taken as soon as possible within 72 hours of unprotected intercourse.

Levonorgestrel 2-dose regimen: 0.75-mg dose taken as soon as possible within 72 hours of unprotected intercourse, followed by a second 0.75-mg dose 12 hours after the first dose.

If necessary, the first dose of either the single or 2-dose regimen can be administered up to120 hours after unprotected intercourse, but efficacy decreases the longer initiation of contraception is delayed.

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

FDA has approved Plan B One-Step for OTC status for women of childbearing potential regardless of age. Next Choice One Dose is a prescription-only preparation for women <17 years of age and an OTC preparation for women ≥17 years of age.

Cautions for Progestins

Contraindications

  • Known or suspected pregnancy.

  • Undiagnosed vaginal bleeding.

  • Known or suspected breast cancer.

  • Benign or malignant liver tumor.

  • Liver disease.

  • Current or past history of thrombosis or thromboembolic disorders.

  • Levonorgestrel-releasing intrauterine contraceptive system also is contraindicated in women with uterine abnormalities that distort the uterine cavity (e.g., fibroids), PID or history of PID (unless there has been a subsequent intrauterine pregnancy), postpartum endometritis or infected abortion in the past 3 months, untreated acute cervicitis or vaginosis, conditions associated with immune compromise (e.g., HIV, leukemia, IV drug abuse), a previously inserted IUD still in place, genital actinomycosis, history of ectopic pregnancy or predisposition for ectopic pregnancy, known or suspected uterine or cervical neoplasia, abnormal Papanicolaou test (Pap smear), and in women with multiple sexual partners or whose partners have multiple sexual partners.

  • Postcoital (emergency) contraception: Currently no real contraindication to postcoital (emergency) contraception with recommended levonorgestrel regimens and benefits generally outweigh any theoretical or proven risk.

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

Warnings/Precautions

Warnings

Ectopic Pregnancy

Consider the possibility of ectopic pregnancy if pregnancy or severe lower abdominal pain occurs in women using progestin contraception, including those using postcoital (emergency) regimens. Follow-up physical or pelvic examination recommended if there are questions about general health or pregnancy status of women after levonorgestrel administration. Current evidence does not support increased risk of ectopic pregnancy after use of levonorgestrel for postcoital (emergency) contraception in the general population; rather, preventing pregnancy overall actually reduces absolute risk. Postcoital contraception with levonorgestrel can be used in women with history of ectopic pregnancy.

Existing Pregnancy

Levonorgestrel 0.75 or 1.5 mg used for postcoital (emergency) contraception is not effective in terminating an existing pregnancy.

Ovarian Follicles

Possible delayed atresia of ovarian follicles, resulting in follicular enlargement. Follicular enlargement generally is asymptomatic or associated with mild abdominal pain and resolves spontaneously; in rare cases, surgery may be required.

Bleeding Irregularities

Possible breakthrough bleeding or irregular vaginal bleeding. Perform adequate diagnostic tests in patients with undiagnosed vaginal bleeding. Rule out pregnancy in patients with amenorrhea. If pregnancy occurs, discontinue therapy.

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

Carcinoma of Breast and Reproductive Organs

Insufficient data to determine whether use of progestin-only contraceptives is associated with an increased risk of breast cancer or cervical carcinoma. (See Contraindications under Cautions.)

Hepatic Effects

Insufficient data to determine whether use of progestin-only contraceptives is associated with increased risk of hepatocellular carcinoma. (See Contraindications and also see Hepatic Impairment under Cautions.)

Implant Considerations

Carefully follow recommended procedures for insertion and removal of implant to minimize potential for complications.

If infection develops at insertion site, initiate appropriate treatment; if infection persists, remove the implant.

Intrauterine Device Considerations

Evaluate women for suitability (i.e., exclude pregnancy; evaluate for genital infections, risk for ectopic pregnancy, and/or PID) prior to insertion of levonorgestrel-releasing intrauterine device. Insert the device under strict aseptic conditions.

Possible complications include intrauterine pregnancy with the device in place; if this occurs, remove device to reduce possibility of complications to the woman (e.g., septicemia, septic shock, death) and fetus (e.g., miscarriage, sepsis, premature labor, premature delivery). Long-term effects unknown if pregnancy is continued with the intrauterine device in place. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Sepsis following insertion of the device reported rarely. Increased risk of infective endocarditis in women with valvular or congenital heart disease and in those with surgically constructed systemic-pulmonary shunts; prophylactic anti-infective therapy recommended at time of insertion for women with congenital heart disease.

Other complications include penetration or embedment of the device in the myometrium and perforation of the uterus or cervix.

Fetal/Neonatal Morbidity and Mortality

Congenital abnormalities reported infrequently in neonates born to women with a levonorgestrel-releasing intrauterine device in place during the pregnancy.

Thromboembolic Disorders

Thromboembolic events (i.e., pulmonary embolism, stroke) reported in patients using etonogestrel implant (Implanon).

General Precautions

Physical Examination and Follow-up

Annual medical history and physical examination advised with long-term progestin therapy. Physical examination may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. Physical examination not required prior to initiating therapy with oral levonorgestrel for postcoital (emergency) contraception. Perform complete medical examination prior to initiating therapy with etonogestrel implant or levonorgestrel-releasing intrauterine system. Exercise particular care in women with family history of breast cancer or those who have breast nodules.

Metabolic Effects

Slight deterioration in glucose tolerance and increases in plasma insulin reported. Monitor prediabetic and diabetic patients.

Altered lipid metabolism (decreased HDL, HDL2, apolipoprotein A-I and A-II; increased hepatic lipase) noted; no change in total cholesterol, LDL, VLDL, or HDL3 observed. Closely monitor women with hyperlipidemia.

Ocular Effects

Obtain ophthalmologist assessment for contact lens wearers who develop visual disturbances or changes in lens tolerance.

Depression

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

Headache

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

HIV and STDs

Does not protect against HIV infection or other sexually transmitted diseases (STDs).

Fertility Following Use

Rapid return of fertility likely following levonorgestrel use for emergency contraception. Continue or initiate routine methods of contraception as soon as possible following levonorgestrel to ensure ongoing pregnancy prevention.

Specific Populations

Pregnancy

Levonorgestrel-releasing intrauterine contraceptive system (Mirena): Category X.

Rule out pregnancy prior to initiating therapy. Rule out pregnancy in patients with amenorrhea. If pregnancy occurs, discontinue therapy.

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

Most studies have revealed no effects on fetal development associated with long-term use of oral progestin contraceptives.

Lactation

Small amounts of progestins are distributed into milk. Adverse effects, such as jaundice, reported rarely in infants.

Postcoital (emergency) contraception: Breast-feeding can continue without restriction during postcoital contraceptive regimens.

Pediatric Use

Safety and efficacy of progestin contraceptives established in women of reproductive age. Safety and efficacy of long-term progestin contraceptives expected to be identical for postpubertal adolescents <16 years of age and women ≥16 years of age. Safety and efficacy of progestin emergency contraceptives expected to be identical for postpubertal adolescents <17 years of age and women ≥17 years of age. Not indicated before menarche.

Geriatric Use

Progestin contraceptives not evaluated in women >65 years of age; not indicated for use in postmenopausal women.

Hepatic Impairment

Steroid hormones (including oral contraceptives) may be poorly metabolized in patients with hepatic dysfunction; use with caution in those individuals. (See Contraindications under Cautions.)

Postcoital (emergency) contraception: No precautions appear necessary with short-term postcoital contraceptive regimens; benefits outweigh any theoretical or known risk.

Common Adverse Effects

Norethindrone tablets: Bleeding irregularities (e.g., frequent or irregular bleeding), headache, breast tenderness, nausea, dizziness.

Levonorgestrel tablets: Nausea, abdominal pain, fatigue, headache, menstrual changes (e.g., heavier or lighter menstrual bleeding), dizziness, breast tenderness. Postcoital (emergency) contraceptive regimens better tolerated with levonorgestrel than with estrogen-progestins.

Etonogestrel implants: Bleeding irregularities (e.g., frequent, heavy, or prolonged bleeding, spotting).

Levonorgestrel-releasing intrauterine system: 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 Pap smear, sinusitis.

Interactions for Progestins

Specific Drugs

Drug

Interaction

Anticonvulsants (carbamazepine, felbamate, oxcarbazepine, phenytoin, topiramate)

Possible reduced contraceptive efficacy

Antifungal agents, azole

Possible increased plasma concentrations of contraceptive steroids with itraconazole or ketoconazole

Anti-infective agents

Interaction unlikely with most anti-infective agents

Antiretroviral agents

Possible changes in pharmacokinetics of orally administered progestins with some HIV protease inhibitors

Barbiturates

Possible reduced contraceptive efficacy

Bosentan

Possible reduced contraceptive efficacy

Griseofulvin

Possible reduced contraceptive efficacy

Modafinil

Possible reduced contraceptive efficacy

Rifampin

Possible reduced contraceptive efficacy

St. John’s wort (Hypericum perforatum)

Possible reduced contraceptive efficacy

Progestins Pharmacokinetics

Absorption

Bioavailability

Levonorgestrel: Rapidly absorbed following oral administration with peak plasma concentrations achieved in 1.6–1.7 hours. Bioavailability is about 100%.

Norethindrone: Rapidly absorbed following oral administration with peak plasma concentrations achieved in 1–2 hours.

Etonogestrel: Approximately 100% bioavailable following sub-Q administration. Following sub-Q insertion of etonogestrel implant, the drug is released at a rate of 60–70 mcg/day at week 5–6, 35–45 mcg/day at the end of year one, 30–40 mcg/day at the end of year two, and 25–30 mcg/day at the end of year three. Peak serum concentrations achieved in a few weeks following insertion of the implant.

Levonorgestrel: Following insertion of a levonorgestrel-containing intrauterine system, drug is released into the uterine cavity at a rate of 20 mcg/day; rate of drug release decreases over time to about 10 mcg/day after 5 years of use.

Food

Effect of food on oral bioavailability not studied.

Distribution

Extent

Distributed into human milk.

Plasma Protein Binding

Levonorgestrel: About 97.5–99% bound to serum proteins, mainly sex hormone binding globulin (SHBG) and to a lesser extent, albumin.

Norethindrone: 61% bound to albumin and 36% bound to SHBG.

Etonogestrel: 66% bound to albumin and 32% bound to SHBG.

Elimination

Metabolism

Etonogestrel is metabolized in the liver by CYP3A4.

Norethindrone is metabolized mainly by reduction, followed by sulfate and glucuronide conjugation.

Elimination Route

Progestins are excreted in urine and feces, principally as metabolites and glucuronide and sulfate conjugates.

Half-life

Levonorgestrel (single oral dose): 24.4–27.5 hours.

Norethindrone (single oral dose): Approximately 8 hours.

Etonogestrel: Approximately 25 hours.

Stability

Storage

Oral

Tablets

Levonorgestrel: 20–25°C.

Norethindrone: 25°C (may be exposed to 15–30°C).

Implant

Etonogestrel implant (Implanon): 25°C (may be exposed to 15–30°C). Protect from light; avoid direct sunlight.

Intrauterine System

Actions

  • Progestin contraceptives produce contraceptive effects by suppressing ovulation, thickening cervical mucus (thus inhibiting sperm migration into the uterus), lowering mid-cycle LH and FSH peaks, slowing ovum movement through the fallopian tubes, and/or alteration of the endometrium.

  • Progestin contraceptives administered after intercourse (postcoital) produce contraceptive effects by inhibiting or delaying ovulation or fertilization. Recent evidence suggests that any endometrial effects are insufficient to prevent implantation. Effects on ovulation alone cannot explain efficacy of postcoital (emergency) contraceptive; interference of sperm transport or penetration and/or impairment of corpus luteum function proposed as contributing factors. Only effective before pregnancy is established; not effective after implantation of a fertilized ovum.

Advice to Patients

  • Importance of reading the manufacturer’s patient information.

  • Importance of taking progestin-only oral contraceptives at the same time each day, without interruption (including during all bleeding episodes).

  • Importance of using a backup method of contraception (e.g., condoms, spermicides) for each sexual encounter during the next 48 hours when a progestin-only oral contraceptive dose is ≥3 hours late.

  • Levonorgestrel 2-dose regimen for postcoital (emergency) contraception: Importance of scheduling the initial dose as soon as possible (within 72 hours after intercourse) and of taking the second dose 12 hours after the initial dose.

  • Postcoital (emergency) contraception: Therapy can be initiated up to 120 hours after intercourse if necessary, but advise of decreased efficacy as time from intercourse to initiation of contraception increases.

  • Postcoital (emergency) contraception: Importance of consulting clinician about alternative methods of contraception if postcoital contraception is used repeatedly.

  • Importance of informing women that progestin-only contraceptives, like all nonbarrier contraceptive methods, do not protect against HIV infection or other sexually transmitted diseases.

  • Importance of advising patients of anticipated menstrual effects.

  • Importance of women informing a clinician if prolonged (i.e., >8 days) or unusually heavy bleeding, amenorrhea, or severe abdominal pain occurs.

  • Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed. Nursing women can continue to breast-feed without restriction during postcoital (emergency) contraceptive regimens.

  • Importance of women informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

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 OTC status for women ≥17 years of age; the contraceptive remains a prescription-only preparation for women <17 years of age.

Etonogestrel

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Implant

68 mg

Implanon

Organon

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Levonorgestrel

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Intrauterine

Intrauterine System

52 mg

Mirena

Berlex

Oral

Tablets

0.75 mg*

Levonorgestrel Tablets (available in pack of 2 tablets)

Perrigo

1.5 mg*

Fallback Solo

Lupin

Levonorgestrel Tablets

Next Choice One Dose

Actavis

Opcicon One-Step

Sun

Plan B One-Step

Teva

Norethindrone (Norethisterone)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

0.35 mg

Micronor

Ortho-McNeil

Nor-Q.D.

Watson

AHFS DI Essentials™. © Copyright 2022, Selected Revisions March 1, 2016. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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