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Levonorgestrel

PubChem Reference Collection SID
PubChem CID
Not available because this is not a discrete structure.
Synonyms
  • Levonorgestrel
  • Levonorgestrel (USAN:USP:INN:BAN)
  • 797-63-7
  • Liletta
  • Skyla
Description
Levonorgestrel (LNG) is a synthetic progestogen similar to [Progesterone] used in contraception and hormone therapy. Also known as Plan B, it is used as a single agent in emergency contraception, and as a hormonal contraceptive released from an intrauterine device, commonly referred to as an IUD. Some of these devices are known as Jaydess, Kyleena, and Mirena. A subdermal implant of levonorgestrel that slowly releases the hormone over a long-term period is also available. In addition to the above uses, levonorgestrel is used as a component of long-term combination contraceptives. Globally, levonorgestrel is the most commonly used emergency contraceptive. It was initially granted FDA approval in 1982 and was the first emergency contraceptive containing only progesterone, showing high levels of efficacy and a lack of estrogenic adverse effects when compared to older emergency contraceptive regimens.
Levonorgestrel is a Progestin and Progestin-containing Intrauterine System. The physiologic effect of levonorgestrel is by means of Inhibit Ovum Fertilization.
Levonorgestrel is the levorotatory form of norgestrel and synthetic progestogen with progestational and androgenic activity. Levonorgestrel binds to the progesterone receptor in the nucleus of target cells, thereby stimulating the resulting hormone-receptor complex, initiating transcription, and increasing the synthesis of certain proteins. This results in a suppression of luteinizing hormone (LH) activity and an inhibition of ovulation, as well as an alteration in the cervical mucus and endometrium.
See also: Norgestrel (broader); Estradiol; levonorgestrel (component of) ... View More ...

1 Synonyms

  • Levonorgestrel
  • Levonorgestrel (USAN:USP:INN:BAN)
  • 797-63-7
  • Liletta
  • Skyla
  • 13-Ethyl-17-hydroxy-18,19-dinor-17alpha- pregn-4-en-20-yn-3-one
  • 5W7SIA7YZW
  • Fallback Solo
  • Kyleena
  • Levonorgestrelum
  • Plan B One-Step
  • 17-Ethynyl-18-methyl-19-nortestosterone
  • 18-Methylnorethisterone
  • Athentia Next
  • Her Style
  • Jadelle
  • Opcicon One-Step
  • (-)-13-ETHYL-17-HYDROXY-18,19-DINOR-17alpha-PREGN-4-EN-20-YN-3-ONE
  • (17alpha)-13-Ethyl-17-hydroxy-18,19-dinorpregn-4-en-20-yn-3-one
  • 13-Ethyl-17-alpha-ethynyl-17-beta-hydroxy-4-gonen-3-one
  • 13-Ethyl-17-alpha-ethynylgon-4-en-17-beta-ol-3-one
  • 17alpha-Ethynyl-13beta-ethyl-3-oxo-4-estren-17beta-ol
  • 17alpha-Ethynyl-17-hydroxy-18-methylestr-4-en-3-one
  • 17alpha-Ethynyl-18-homo-19-nortestosterone
  • 18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-, (17alpha)-(-)-
  • 18-Methyl-17-alpha-ethynyl-19-nortestosterone
  • D-Norgestrel
  • Norplant system in plastic container
  • Wy-5104
  • (-)-Norgestrel
  • 13-Ethyl-17alpha-ethynyl-17-hydroxygon-4-en-3-one
  • 13-Ethyl-17alpha-ethynylgon-4-en-17beta-ol-3-one
  • 13-beta-Ethyl-17alpha-ethynyl-17beta-hydroxygon-4-en-3-one
  • 17-alpha-Ethynyl-13-ethyl-19-nortestosterone
  • 212-349-8
  • AfterPill
  • AfterPlan
  • Aftera
  • BAY86-5028
  • CHEBI:6443
  • Curae
  • D-(-)-Norgestrel
  • EContra One-Step
  • Econ Morning After
  • Emergency Contraceptive
  • Fem Choice morning after
  • ITHAPPENZ MORNING AFTER
  • Julie
  • LEADER Emergency Contraceptive Levonorgestrel
  • Levonorgestrel Tablet, 1.5 mg
  • Levonova
  • Morning After
  • My Choice TM
  • My Way
  • New Day
  • Next Choice
  • Next Choice One Dose
  • Option 2
  • Optionelle
  • PostDay One-Step
  • SheWise
  • Stix Restart
  • Take Action
  • basic care levonorgestrel
  • d(-)-Norgestrel
  • (8R,9S,10R,13S,14S,17R)-13-ethyl-17-ethynyl-17-hydroxy- 1,2,6,7,8,9,10,11,12,13,14,15,16, 17- tetradecahydrocyclopenta(a) phenanthren-3-one
  • 13-Ethyl-17-ethynyl-17beta-hydroxy-4-gonen-3-one
  • 13alpha-ethyl-17alpha-ethynyl-17beta-hydroxygon-4-en-3-one
  • 13beta-Ethyl-17alpha-ethynyl-17beta-hydroxygon-4-en-3-one
  • 17-beta-Hydroxy-18-methyl-19-nor-17-alpha-pregn-4-en-20-yn-3-one
  • 17alpha-Ethynyl-13-ethyl-19-nortestosterone
  • 17alpha-ethynyl-17beta-hydroxy-18a-homoestr-4-en-3-one
  • 18,19-Dinor-17-alpha-pregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-
  • 18-Methylnorethindrone
  • 19-Nortestosterone, 17-ethynyl-18-methyl-
  • AFIRMELLE COMPONENT LEVONORGESTREL
  • ALESSE COMPONENT LEVONORGESTREL
  • ALTAVERA COMPONENT LEVONORGESTREL
  • AVIANE COMPONENT LEVONORGESTREL
  • After Banger
  • BAY 86-5028
  • BRN 2391114
  • CCRIS 6525
  • CLIMARA PRO COMPONENT LEVONORGESTREL
  • D Norgestrel
  • D-l-Norgestrel
  • DTXCID1016496
  • DTXSID3036496
  • E-Gen-C
  • EINECS 212-349-8
  • ELIFEMME COMPONENT LEVONORGESTREL
  • ENPRESSE COMPONENT LEVONORGESTREL
  • Empowered Choice
  • G03AC03
  • G03AD01
  • HSDB 6483
  • IMPLANT WITH LEVONORGESTREL
  • INTROVALE COMPONENT LEVONORGESTREL
  • Intrauterine levonorgestrel
  • KURVELO COMPONENT LEVONORGESTREL
  • KYLEENA COMPONENT LEVONORGESTREL
  • LESSINA COMPONENT LEVONORGESTREL
  • LEVLITE COMPONENT LEVONORGESTREL
  • LEVONEST COMPONENT LEVONORGESTREL
  • LEVONORGESTREL (EP MONOGRAPH)
  • LEVONORGESTREL (MART.)
  • LEVONORGESTREL (USP IMPURITY)
  • LEVONORGESTREL (USP MONOGRAPH)
  • LEVONORGESTREL (USP-RS)
  • LEVONORGESTREL COMPONENT OF ALESSE
  • LEVONORGESTREL COMPONENT OF ALTAVERA
  • LEVONORGESTREL COMPONENT OF CLIMARA PRO
  • LEVONORGESTREL COMPONENT OF INTROVALE
  • LEVONORGESTREL COMPONENT OF KYLEENA
  • LEVONORGESTREL COMPONENT OF LEVLITE
  • LEVONORGESTREL COMPONENT OF LEVONEST
  • LEVONORGESTREL COMPONENT OF LOSEASONIQUE
  • LEVONORGESTREL COMPONENT OF LYBREL
  • LEVONORGESTREL COMPONENT OF OPCICON ONE-STEP
  • LEVONORGESTREL COMPONENT OF PREVEN
  • LEVONORGESTREL COMPONENT OF QUASENSE
  • LEVONORGESTREL COMPONENT OF SEASONALE
  • LEVONORGESTREL COMPONENT OF SEASONIQUE
  • LEVONORGESTREL COMPONENT OF SETLAKIN
  • LEVONORGESTREL COMPONENT OF TWIRLA
  • LEVORA COMPONENT LEVONORGESTREL
  • LNG-IUS
  • LOSEASONIQUE COMPONENT LEVONORGESTREL
  • LYBREL COMPONENT LEVONORGESTREL
  • Levlen ED
  • Levogel
  • Levonelle
  • Levonorgestrel 1.5 mg
  • Levonorgestrel implant
  • Levonorgestrelum (INN-Latin)
  • Levora-21
  • Levora-28
  • Levosert
  • Logynon ED
  • MARLISSA COMPONENT LEVONORGESTREL
  • MYZILRA COMPONENT LEVONORGESTREL
  • Microgest ED
  • Microgyn
  • Microgynon 21
  • Microgynon 28
  • Microgynon 30 ED
  • Microgynon CD
  • Microlution
  • Microluton
  • Monofeme 28
  • NORDETTE COMPONENT LEVONORGESTREL
  • NORGESTIMATE IMPURITY B (EP IMPURITY)
  • NORGESTREL (-)-FORM
  • NORGESTREL, (-)-
  • NSC 744007
  • NSC 759653
  • NSC-744007
  • Neogynon 21
  • Nordet
  • Nordette 21
  • Nordette 28
  • Norplant II
  • OPCICON ONE-STEP COMPONENT LEVONORGESTREL
  • ORSYTHIA COMPONENT LEVONORGESTREL
  • Oral levonorgestrel
  • Ovoplex 30-150
  • Ovral-Lo
  • Ovranette
  • PLASTIC IUD WITH LEVONORGESTREL
  • PORTIA COMPONENT LEVONORGESTREL
  • PREVEN COMPONENT LEVONORGESTREL
  • Plan B One Step
  • Preven
  • QUARTETTE COMPONENT LEVONORGESTREL
  • QUASENSE COMPONENT LEVONORGESTREL
  • React
  • Rigevidon 21+7
  • SEASONALE COMPONENT LEVONORGESTREL
  • SEASONIQUE COMPONENT LEVONORGESTREL
  • SETLAKIN COMPONENT LEVONORGESTREL
  • Stediril 30
  • TRIPHASIL COMPONENT LEVONORGESTREL
  • TRIVORA COMPONENT LEVONORGESTREL
  • TWIRLA COMPONENT LEVONORGESTREL
  • Tri-Levlen 21
  • Triagynon
  • Triciclor
  • Trifeme 28
  • Trigoa
  • Trinordiol 21
  • Trinordiol 28
  • Triphasil 21
  • Triphasil 28
  • Triquilar ED
  • UNII-5W7SIA7YZW
  • VIENVA COMPONENT LEVONORGESTREL
  • l Norgestrel
  • levonorgestrel|norgestrel

2 Names and Identifiers

2.1 Other Identifiers

2.1.1 CAS

797-63-7

2.1.2 Deprecated CAS

121714-72-5, 4222-79-1, 797-62-6

2.1.3 European Community (EC) Number

2.1.4 NSC Number

2.1.5 UNII

2.1.6 DSSTox Substance ID

2.1.7 Nikkaji Number

2.1.8 Wikipedia

2.1.9 NCI Thesaurus Code

2.1.10 RXCUI

2.1.11 Pharos Ligand ID

3 Chemical and Physical Properties

3.1 Experimental Properties

3.1.1 Color / Form

Crystals from methanol
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1159
White...crystalline powder
IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: https://monographs.iarc.fr/ENG/Classification/index.php, p. V72: 591 (1999)

3.1.2 Odor

Odorless
IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: https://monographs.iarc.fr/ENG/Classification/index.php, p. V72: 591 (1999)

3.1.3 Boiling Point

3.1.4 Melting Point

232-239
206 °C
Lide, D.R. CRC Handbook of Chemistry and Physics 88TH Edition 2007-2008. CRC Press, Taylor & Francis, Boca Raton, FL 2007, p. 3-400

3.1.5 Solubility

2.05 mg/L
Soluble in ethanol (1 in 120), chloroform (1 in 15), diethyl ether (1 in 400) and dioxane.
IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: https://monographs.iarc.fr/ENG/Classification/index.php, p. V72: 591 (1999)

3.1.6 LogP

3.1.7 LogS

3.1.8 Optical Rotation

Specific optical rotation: -324 deg at 20 °C/D (c = 0.496 in CHCl3)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1159

3.1.9 Decomposition

When heated to decomposition it emits acrid smoke and irritating fumes.
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2748

3.1.10 Dissociation Constants

4 Spectral Information

4.1 Mass Spectrometry

4.1.1 LC-MS

1 of 4
View All
MoNA ID
MS Category
Experimental
MS Type
LC-MS
MS Level
MS2
Precursor Type
[M+H]+
Precursor m/z
313.2162
Instrument
Q Exactive Plus Orbitrap Thermo Scientific
Instrument Type
LC-ESI-QFT
Ionization
ESI
Ionization Mode
positive
Collision Energy
35 (nominal)
Retention Time
11.804 min
Top 5 Peaks

313.2162 100

109.0648 24.16

245.19 12.79

91.0542 9.93

83.0491 9.61

Thumbnail
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License
CC BY
2 of 4
View All
MoNA ID
MS Category
Experimental
MS Type
LC-MS
MS Level
MS2
Precursor Type
[M-H]-
Precursor m/z
311.2017
Instrument
Q Exactive Orbitrap (Thermo Scientific)
Instrument Type
LC-ESI-QFT
Ionization
ESI
Ionization Mode
negative
Collision Energy
90
Retention Time
19.923 min
Top 5 Peaks

149.0972 100

133.066 44.40

119.0503 4.80

277.1607 0.17

Thumbnail
Thumbnail
License
CC0

6 Drug and Medication Information

6.1 Drug Indication

**Emergency contraception** Levonorgestrel, in the single-agent emergency contraceptive form, is indicated for the prevention of pregnancy after the confirmed or suspected failure of contraception methods or following unprotected intercourse. It is distributed by prescription for patients under 17, and over the counter for those above this age. This levonorgestrel-only form of contraception is not indicated for regular contraception and must be taken as soon as possible within 72 hours after intercourse. It has shown a lower efficacy when it is used off label within 96 hours. **Long-term contraception or nonemergency contraception** In addition to the above indication in emergency contraception, levonorgestrel is combined with other contraceptives in contraceptive formulations designed for regular use, for example with ethinyl estradiol. It is used in various hormone-releasing intrauterine devices for long-term contraception ranging for a duration of 3-5 years. Product labeling for Mirena specifically mentions that it is recommended in women who have had at least 1 child and can be indicated for the prevention of pregnancy for up to 8 years. A subdermal implant is also available for the prevention of pregnancy for up to 5 years. **Hormone therapy and off-label uses** Levonorgestrel is prescribed in combination with estradiol as hormone therapy during menopause to manage vasomotor symptoms and to prevent osteoporosis.Off-label, levonorgestrel may be used to treat menorrhagia, endometrial hyperplasia, and endometriosis.
Prevention of pregnancy
Contraception

6.2 Drug Classes

Breast Feeding; Lactation; Milk, Human; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic
Breast Feeding; Lactation; Milk, Human; Contraceptive Agents, Female
Breast Feeding; Lactation; Milk, Human; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; Contraceptives, Postcoital

6.3 WHO Essential Medicines

Drug
Drug Classes
Intrauterine devices
Formulation
Intrauterine system with reservoir containing 52 mg of levonorgestrel.
Indication
Contact with health services for insertion of contraceptive device
Drug
Drug Classes
Oral hormonal contraceptives
Formulation
(1) Oral - Solid: 750 µg [2]; 1.5 mg [1]; (2) Oral - Solid: 30 µg
Indication
(1) Contact with health services for postcoital contraception; (2) Contact with health services for contraceptive management

6.4 FDA Approved Drugs

6.5 FDA Orange Book

6.6 FDA National Drug Code Directory

6.7 Drug Labels

Drug and label
Active ingredient and drug

6.8 EMA Drug Information

1 of 2
Type
Paediatric investigation
Active Substance
Therapeutic Area
Endocrinology-Gynaecology-Fertility-Metabolism
Drug Form
Vaginal delivery system
Administration Route
Vaginal use
Decision Type
PM: decision on the application for modification of an agreed PIP
Decision Date
2022-10-28
2 of 2
Type
Paediatric investigation
Active Substance
Therapeutic Area
Endocrinology-Gynaecology-Fertility-Metabolism
Drug Form
Intrauterine delivery system
Administration Route
Intrauterine use
Decision Type
P: decision agreeing on a investigation plan, with or without partial waiver(s) and or deferral(s)
Decision Date
2010-05-05

6.9 Therapeutic Uses

Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; Progestational Hormones, Synthetic
National Library of Medicine's Medical Subject Headings online file (MeSH, 2009)
Aviane is indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception. /Included in US product label/
US Natl Inst Health; DailyMed. Current Medication Information for AVIANE (levonorgestrel and ethinyl estradiol) kit (September 2009). Available from, as of February 5, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=14957
Next Choice is a progestin-only emergency contraceptive indicated for prevention of pregnancy following unprotected intercourse or a known or suspected contraceptive failure. To obtain optimal efficacy, the first tablet should be taken as soon as possible within 72 hours of intercourse. The second tablet should be taken 12 hours later. /Included in US product label/
US Natl Inst Health; DailyMed. Current Medication Information for NEXT CHOICE (levonorgestrel) tablet (December 2009). Available from, as of February 5, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=14292
Mirena is indicated for the treatment of heavy menstrual bleeding in women who choose to use intrauterine contraception as their method of contraception. /Included in US product label/
US Natl Inst Health; DailyMed. Current Medication Information for MIRENA (levonorgestrel) intrauterine device (May 2009). Available from, as of February 5, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=11844
For more Therapeutic Uses (Complete) data for LEVONORGESTREL (7 total), please visit the HSDB record page.

6.10 Drug Warnings

/BOXED WARNING/ WARNINGS: Estrogens and progestins should not be used for the prevention of cardiovascular disease or dementia. The Women's Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo. The WHI study reported increased risks of stroke and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 6.8 years of treatment with oral conjugated estrogens (CE 0.625 mg) relative to placebo. The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with CE 0.625 mg combined with MPA 2.5 mg and during 5.2 years of treatment with CE 0.625 mg alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
US Natl Inst Health; DailyMed. Current Medication Information for CLIMARA PRO (estradiol and levonorgestrel) patch (June 2009). Available from, as of February 10, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=34043
Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with the extent of smoking (in epidemiologic studies, 15 or more cigarettes per day was associated with a significantly increased risk) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.
US Natl Inst Health; DailyMed. Current Medication Information for MIRENA (levonorgestrel) intrauterine device (May 2009). Available from, as of February 5, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=11844
Use of oral contraceptives is associated with an increased risk of several serious conditions including thromboembolism, stroke, myocardial infarction, liver tumor, gallbladder disease, visual disturbances, fetal abnormalities, and hypertension. Cigarette smoking increases the risk of serious adverse cardiovascular effects during oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes daily) and is markedly greater in women older than 35 years of age. Women who are receiving estrogen-progestin contraceptives should be strongly advised not to smoke. Women older than 35 years of age who smoke, and women with ischemic heart disease or a history of this disease, should not use estrogen-progestin contraceptives. Estrogen-progestin contraceptives should be used with caution in women with cardiovascular disease risk factors.
American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3112
In general, no adverse effects of progestin-only pills have been found on breastfeeding performance or on the health, growth or development of the infant. However, isolated post-marketing cases of decreased milk production have been reported.
US Natl Inst Health; DailyMed. Current Medication Information for NEXT CHOICE (levonorgestrel) tablet (December 2009). Available from, as of February 5, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=14292
For more Drug Warnings (Complete) data for LEVONORGESTREL (52 total), please visit the HSDB record page.

7 Pharmacology and Biochemistry

7.1 Pharmacodynamics

Levonorgestrel prevents pregnancy by interfering with ovulation, fertilization, and implantation. The levonorgestrel-only containing emergency contraceptive tablet is 89% effective if it is used according to prescribing information within 72 hours after intercourse. The intrauterine and implantable devices releasing levonorgestrel are more than 99% in preventing pregnancy. Levonorgestrel utilized as a component of hormonal therapy helps to prevent endometrial carcinoma associated with unopposed estrogen administration.

7.2 FDA Pharmacological Classification

1 of 4
FDA UNII
5W7SIA7YZW
Active Moiety
LEVONORGESTREL
Pharmacological Classes
Physiologic Effects [PE] - Inhibit Ovum Fertilization
Pharmacological Classes
Chemical Structure [CS] - Progesterone Congeners
Pharmacological Classes
Chemical Structure [CS] - Progesterone Congeners
Pharmacological Classes
Established Pharmacologic Class [EPC] - Progestin
Pharmacological Classes
Established Pharmacologic Class [EPC] - Progestin-containing Intrauterine System
FDA Pharmacology Summary
Levonorgestrel is a Progestin and Progestin-containing Intrauterine System. The physiologic effect of levonorgestrel is by means of Inhibit Ovum Fertilization.
2 of 4
Non-Proprietary Name
LEVONORGESTREL
Pharmacological Classes
Inhibit Ovum Fertilization [PE]; Progestin-containing Intrauterine System [EPC]; Progestin [EPC]; Progestin-containing Intrauterine Device [EPC]; Progesterone Congeners [CS]
3 of 4
Non-Proprietary Name
LEVONORGESTREL 1.5 MG
Pharmacological Classes
Progestin-containing Intrauterine System [EPC]; Inhibit Ovum Fertilization [PE]; Progesterone Congeners [CS]; Progestin [EPC]
4 of 4
Non-Proprietary Name
LEVONORGESTREL TABLET, 1.5 MG
Pharmacological Classes
Inhibit Ovum Fertilization [PE]; Progestin [EPC]; Progestin-containing Intrauterine Device [EPC]; Progesterone Congeners [CS]

7.3 ATC Code

G - Genito urinary system and sex hormones

G03 - Sex hormones and modulators of the genital system

G03A - Hormonal contraceptives for systemic use

G03AC - Progestogens

G03AC03 - Levonorgestrel

G - Genito urinary system and sex hormones

G03 - Sex hormones and modulators of the genital system

G03A - Hormonal contraceptives for systemic use

G03AD - Emergency contraceptives

G03AD01 - Levonorgestrel

G03AD01; G02BA03; G03AC03

7.4 Absorption, Distribution and Excretion

Absorption
Orally administered levonorgestrel is absorbed in the gastrointestinal tract while levonorgestrel administered through an IUD device is absorbed in the endometrium. Levonorgestrel is absorbed immediately in the interstitial fluids when it is inserted as a subdermal implant. After insertion of the subdermal implant, the Cmax of levonorgestrel is attained within 2-3 days.The Cmax following one dose of 0.75 mg of oral levonorgestrel is reached within the hour after administration, according to one reference. In a pharmacokinetic study of 1.5 mg of levonorgestrel in women with a normal BMI and those considered to be obese (BMI>30), mean Cmax was found to be 16.2 ng/mL and 10.5 ng/mL respectively. Tmax was found to be 2 hours for those with normal BMI and 2.5 hours for patients with increased BMI. The bioavailability of levonorgestrel approaches 100%. Mean AUC has been shown to be higher in patients with a normal BMI, measuring at 360.1 h × ng/mL versus a range of 197.28 to 208.1 h × ng/mL in an obese group of patients. Obesity may contribute to decreased efficacy of levonorgestrel in contraception.
Route of Elimination
Approximately 45% of an oral levonorgestrel dose and its conjugated or sulfate metabolites are found to be excreted in the urine. Approximately 32% of an orally ingested dose is found excreted in feces, primarily in the form of glucuronide conjugates of levonorgestrel.
Volume of Distribution
One pharmacokinetic study determined a mean steady-state volume of distribution of 1.5 mg of levonorgestrel to be 162.2 L in those with normal BMI and in the range of 404.7 L to 466.4 L in obese patients with a body mass index of at least 30. Mean volume of distribution in 16 patients receiving 0.75 mg of levonorgestrel in another pharmacokinetic study was 260 L. The Plan B one-step FDA label reports an apparent volume of distribution of 1.8 L/kg.
Clearance
Clearance was found to 4.8 L/h in healthy female volunteers with a normal BMI, and 7.70-8.51 L/h in obese patients after a single 1.5 mg dose. After a 0.75 mg dose of levonorgestrel in 16 patients in another pharmacokinetic study, mean clearance was calculated at 7.06 L/h. Following levonorgestrel implant removal, the serum concentration falls below 100 pg/mL within the first 96 hours and further falls below the sensitivity of detection within the range of 5 days to 2 weeks.
The apparent volume of distribution of levonorgestrel is reported to be approximately 1.8 L/kg. It is about 97.5 to 99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin.
US Natl Inst Health; DailyMed. Current Medication Information for NEXT CHOICE (levonorgestrel) tablet (December 2009). Available from, as of February 5, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=14292
No specific investigation of the absolute bioavailability of Aviane (levonorgestrel and ethinyl estradiol tablets, USP) in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability about 100%) and is not subject to first-pass metabolism.
US Natl Inst Health; DailyMed. Current Medication Information for AVIANE (levonorgestrel and ethinyl estradiol) kit (September 2009). Available from, as of February 5, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=14957
After a single dose of levonorgestrel and ethinyl estradiol 0.10 mg/0.02 mg tablets to 22 women under fasting conditions, maximum serum concentrations of levonorgestrel are 2.8 +/- 0.9 ng/mL (mean +/- SD) at 1.6 +/- 0.9 hours. At steady-state, attained from day 19 onwards, maximum levonorgestrel concentrations of 6 +/- 2.7 ng/mL are reached at 1.5 +/- 0.5 hours after the daily dose. The minimum serum levels of levonorgestrel at steady-state are 1.9 +/- 1 ng/mL. Observed levonorgestrel concentrations increased from day 1 (single dose) to days 6 and 21 (multiple doses) by 34% and 96%, respectively. Unbound levonorgestrel concentrations increased from day 1 to days 6 and 21 by 25% and 83%, respectively. The kinetics of total levonorgestrel are nonlinear due to an increase in binding of levonorgestrel to sex hormone binding globulin (SHBG), which is attributed to increased SHBG levels that are induced by the daily administration of ethinyl estradiol.
US Natl Inst Health; DailyMed. Current Medication Information for AVIANE (levonorgestrel and ethinyl estradiol) kit (September 2009). Available from, as of February 5, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=14957
The bioavailability of levonorgestrel is generally accepted to be 100%. This generalization is based on two studies that used only a small number of women. In one of the studies, absolute bioavailabilities were determined for doses of 0.25 and 0.15 mg levonorgestrel, each of which was administered to five women in combination with ethinylestradiol (0.05 mg). The results show that the bioavailability for the 0.15-mg dose of levonorgestrel ranged from 72 to 125% (mean, 99%); that for the 0.15-mg dose ranged from 63 to 108% (mean, 89%).
IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: https://monographs.iarc.fr/ENG/Classification/index.php, p. V91 147 (2007)
For more Absorption, Distribution and Excretion (Complete) data for LEVONORGESTREL (14 total), please visit the HSDB record page.

7.5 Metabolism / Metabolites

After absorption of the oral emergency contraceptive preparation, levonorgestrel is conjugated and forms a large number of sulfate conjugates. In addition, glucuronide conjugates have been identified in the plasma. High levels of conjugated and unconjugated 3α, 5β-tetrahydrolevonorgestrel are found in the plasma. The entire metabolic pathway for levonorgestrel has not been studied, however, 16β-hydroxylation is one pathway that has been identified. Small quantities of 3α, 5α­ tetrahydrolevonorgestrel and 16βhydroxylevonorgestrel are also formed. No active metabolites have been identified. The rate of metabolism may be considerably different according to the patient and may explain a wide variation in levonorgestrel clearance. Liver CYP3A4 and CYP3A5 hepatic enzymes are reported to be involved in the metabolism of levonorgestrel.
Following absorption, levonorgestrel is conjugated at the 17beta-OH position to form sulfate conjugates and, to a lesser extent, glucuronide conjugates in plasma. Significant amounts of conjugated and unconjugated 3alpha, 5beta-tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3alpha, 5alpha-tetrahydrolevonorgestrel and 16beta-hydroxylevonorgestrel. Levonorgestrel and its phase I metabolites are excreted primarily as glucuronide conjugates. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users.
US Natl Inst Health; DailyMed. Current Medication Information for NEXT CHOICE (levonorgestrel) tablet (December 2009). Available from, as of February 5, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=14292
The most important metabolic pathway for levonorgestrel occurs in the reduction of the delta4- and the 3-oxo-group as well as hydroxylations at positions 2alpha , 1beta, and 16beta, followed by conjugation. Most of the metabolites that circulate in the blood are sulfates of 3beta , 5beta -tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. ... In-vitro studies on the biotransformation of levonorgestrel in human skin did not indicate any significant metabolism of levonorgestrel during skin penetration.
US Natl Inst Health; DailyMed. Current Medication Information for CLIMARA PRO (estradiol and levonorgestrel) patch (June 2009). Available from, as of February 10, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=34043
/Investigators/ reviewed the metabolism of levonorgestrel in women treated orally with the radioactively labelled compound. Levonorgestrel was found mostly untransformed in serum within 1-2 hr after administration, but the concentrations of conjugated metabolites increased progressively between 4 and 24 hr after ingestion. Most of the conjugates were sulfates and glucuronides. In addition to the remaining unconjugated levonorgestrel, considerable amounts of unconjugated and sulfate-conjugated forms of 3alpha,5beta- tetrahydrolevonorgestrel were found; smaller quantities of conjugated and unconjugated 3alpha,5beta-tetrahydrolevonorgestrel and 16beta-hydroxylevonorgestrel were also identified. ... The major urinary metabolites were glucuronides (the most abundant was 3alpha,5beta-tetrahydrolevonorgestrel glucuronide) and smaller quantities of sulfates were found.
IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: https://monographs.iarc.fr/ENG/Classification/index.php, p. V91 146 (2007)
In vitro studies were conducted on the metabolism of 3 steroids used in OCs (oral contraceptives) by small pieces of human jejunal mucosa. This was done because the gastrointestinal mucosa of humans is known to metabolize a number of drugs. Almost 40% of the ethinyl estradiol, 9.8% of the levonorgestrel, and 7% of the mestranol were metabolized after incubation. All these metabolic responses were significantly different from those in the control groups. Results of the study show that the metabolism of the ethinyl estradiol was related to the weight of the tissue used. These results are consistent with the known marked 1st pass effect of ethinyl estradiol. Norgestrel, known to have little or no 1st pass effect, did not show a high rate of gut metabolism. Under the experimental conditions employed, no Phase 1 metabolism of either ethinyl estradiol or levonorgestrel was apparent.
Back DJ et al; Br J Clin Pharmacol 11 (3): 275-8 (1981)
For more Metabolism/Metabolites (Complete) data for LEVONORGESTREL (6 total), please visit the HSDB record page.

7.6 Biological Half-Life

The elimination half-life of a 0.75 mg dose of 1.5 mg of levonorgestrel ranges between 20-60 hours post-administration. A pharmacokinetic study of women with a normal BMI and BMI over revealed an elimination half-life of 29.7 h and 41.0-46.4 hours, respectively. Another pharmacokinetic study revealed a mean elimination half-life of 24.4 hours after a 0.75 mg dose of levonorgestrel was administered to 16 patients.
The elimination half-life for levonorgestrel is approximately 36 +/- 13 hours at steady-state.
US Natl Inst Health; DailyMed. Current Medication Information for AVIANE (levonorgestrel and ethinyl estradiol) kit (September 2009). Available from, as of February 5, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=14957
Mean (+/- SD) terminal half-life for levonorgestrel was determined to be 28 +/- 6.4 hours.
US Natl Inst Health; DailyMed. Current Medication Information for CLIMARA PRO (estradiol and levonorgestrel) patch (June 2009). Available from, as of February 10, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=34043
... The mean half-life of elimination was found to be 13.2 hr and 9.9 hr for the 0.15-mg and 0.25-mg doses of levonorgestrel, respectively, when administered intravenously. These values were similar after oral dosing.
IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: https://monographs.iarc.fr/ENG/Classification/index.php, p. V91 147 (2007)

7.7 Mechanism of Action

**Mechanism of action on ovulation** Oral contraceptives containing levonorgestrel suppress gonadotropins, inhibiting ovulation. Specifically, levonorgestrel binds to progesterone and androgen receptors and slows the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. This process results in the suppression of the normal physiological luteinizing hormone (LH) surge that precedes ovulation. It inhibits the rupture of follicles and viable egg release from the ovaries. Levonorgestrel has been proven to be more effective when administered before ovulation. **Mechanism of action in cervical mucus changes** Similar to other levonorgestrel-containing contraceptives, the intrauterine (IUD) forms of levonorgestrel likely prevent pregnancy by increasing the thickness of cervical mucus, interfering with the movement and survival of sperm, and inducing changes in the endometrium, where a fertilized ovum is usually implanted. Levonorgestrel is reported to alter the consistency of mucus in the cervix, which interferes with sperm migration into the uterus for fertilization. Levonorgestrel is not effective after implantation has occurred. Interestingly, recent evidence has refuted the commonly believed notion that levonorgestrel changes the consistency of cervical mucus when it is taken over a short-term period, as in emergency contraception. Over a long-term period, however, levonorgestrel has been proven to thicken cervical mucus. The exact mechanism of action of levonorgestrel is not completely understood and remains a topic of controversy and ongoing investigation. *Effects on implantation** The effects of levonorgestrel on endometrial receptivity are unclear, and the relevance of this mechanism to the therapeutic efficacy of levonorgestrel is contentious. Prescribing information for levonorgestrel IUDs state that they exert local morphological changes to the endometrium (e.g. stromal pseudodecidualization, glandular atrophy) that may play a role in their contraceptive activity. **Mechanism of action in hormone therapy** When combined with estrogens for the treatment of menopausal symptoms and prevention of osteoporosis, levonorgestrel serves to lower the carcinogenic risk of unopposed estrogen therapy via the inhibition of endometrial proliferation. Unregulated endometrial proliferation sometimes leads to endometrial cancer after estrogen use.
Emergency contraceptive pills are not effective if a woman is already pregnant. Levonorgestrel is believed to act as an emergency contraceptive principally by preventing ovulation or fertilization (by altering tubal transport of sperm and/or ova). In addition, they may inhibit implantation (by altering the endometrium). It is not effective once the process of implantation has begun.
US Natl Inst Health; DailyMed. Current Medication Information for NEXT CHOICE (levonorgestrel) tablet (December 2009). Available from, as of February 5, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=14292
The precise mechanism of contraceptive activity of levonorgestrel administered after intercourse (postcoital) is not known. Levonorgestrel has been shown to inhibit or delay ovulation; other mechanisms of action for preventing pregnancy presumably are involved. Levonorgestrel is only effective before pregnancy is established. Once implantation occurs (ie, usually within 6-7 days after ovulation), levonorgestrel is ineffective in preventing pregnancy.
American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3122
Potential noncontraceptive benefits of oral contraceptives, as evidenced from epidemiologic studies, include effects on menses, effects related to inhibition of ovulation, and effects from long-term use. Use of the drugs has been associated with improved menstrual cycle regularity and decreased incidences of blood loss, iron deficiency anemia, and dysmenorrhea. A decreased incidence of functional ovarian cysts and of ectopic pregnancies also has been associated with use of the drugs. Long-term use of oral contraceptives has been associated with a decreased incidence of formation of fibroadenomas and fibrocystic disease of the breast, a decreased incidence of some (eg, gonococcal) pelvic inflammatory disease, and a decreased incidence of some cancers (eg, endometrial or ovarian cancer).
American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3116
Progestins enter target cells by passive diffusion and bind to cytosolic (soluble) receptors that are loosely bound in the nucleus. The steroid receptor complex initiates transcription, resulting in an increase in protein synthesis. /Progestins/
USP. Convention. USPDI - Drug Information for the Health Care Professional. 20th ed. Volume I. Micromedex, Inc. Englewood, CO., 2000. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 2568
For more Mechanism of Action (Complete) data for LEVONORGESTREL (6 total), please visit the HSDB record page.

8 Use and Manufacturing

8.1 Uses

Used as a combined oral contraceptive with ethinylestradiol in monophasic, biphasic, and triphasic regimens. It is also used as a 'progestin-only' contraceptive pill and subdermal implant.
IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: https://monographs.iarc.fr/ENG/Classification/index.php, p. V72 592 (1999)
MEDICATION

8.1.1 Use Classification

Human Drugs -> EU pediatric investigation plans
Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

8.2 Methods of Manufacturing

The activity of norgestrel is found in the levorotatory form D-l-norgestrel or levonorgestrel. Synthesis of the levorotatory form involves meta-cresol methyl ether, dimethyl malonate and trans-1,4-dibromo-2-butene as starting materials. The steroid skeleton was constructed by using an intramolecular Diels-Alder reaction of an ortho-quinodimethane derivative, preceded by photo-enolization of an appropriate methyl-substituted acetophenone derivative. Chirality was introduced at an early stage during a nucleophilic substitution reaction. It is not known if this synthesis is used commercially.
IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: https://monographs.iarc.fr/ENG/Classification/index.php, p. V72 592 (1999)

8.3 Impurities

Reported impurities include: 13-ethyl-3,4-diethynyl-18,19-dinor-17alpha-pregn-5-en-20- yn-3beta,4alpha,17-triol, 13-ethyl-3,4-diethynyl-18,19-dinor-17alpha-pregn-5-en-20-yn-3alpha,4alpha,17- triol 13-ethyl-18,19-dinor-17alpha-pregn-4-en-20-yn-17-ol, 13-ethyl-3-ethynyl-18,19-dinor-17alpha-pregna-3,5-dien-20-yn-17-ol, 13-ethyl-17-hydroxy-18,19-dinor-17alpha-pregna-4,8(14)- dien-20-yn-3-one and 13-ethyl-17-hydroxy-18,19-dinor-17alpha-pregn-5(10)-en-20-yn-3-one.
IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: https://monographs.iarc.fr/ENG/Classification/index.php, p. V91 408 (2007)

8.4 Formulations / Preparations

Levonorgestrel is available commercially as a single-ingredient tablet and in combined tablets with estradiol, estradiol valerate, estriol and ethinylestradiol ... It is also available as an intrauterine system and as a flexible, closed-capsule implant made of silicone rubber tubing.
IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: https://monographs.iarc.fr/ENG/Classification/index.php, p. V91 408 (2007)
Plan B (levonorgestrel) tablets, 0.75 mg, are available for a single course of treatment in PVC/aluminum foil blister packages of two tablets each.
US Natl Inst Health; DailyMed. Current Medication Information for PLAN B (levonorgestrel) tablet (July 2009). Available from, as of February 5, 2010: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=62aace29-36a3-4a2a-aae0-61f7480095c1

8.5 General Manufacturing Information

The activity of norgestrel is found in the levorotatory form D-l-norgestrel or levonorgestrel.
IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: https://monographs.iarc.fr/ENG/Classification/index.php, p. V72 592 (1999)
...was manufactured or formulated in Augentina, Australia, Austria, Belgium, Brazil, Canada, Finland, France, German, India, Mexico, the Netherlands, New Zealand, Portugal, South Africa, Spain, Switzerland, the United Kingdom and the U.S.
IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: https://monographs.iarc.fr/ENG/Classification/index.php, p. V72 592 (1999)

9 Identification

9.1 Analytic Laboratory Methods

Thin layer chromatography. A plate coated with a 0.25 mm layer of chromatographic silica gel mixture is used.
USP Convention. The United States Pharmacopeia XXII/National Formulary XVII. Rockville, MD: United States Pharmacopeial Convention, Inc., 1990., p. 964
Automated stability indicating high performance liquid chromatographic assay for ethinylestradiol and (levo)norgestrel tablets. The UV absorbance of levonorgestrel and norgestrel at 240 nm and the fluorescence of ethinylestradiol at 310.
Reif VD et al; Pharm Res 4 (1): 54-8 (1987)
... Infra-red and ultra-violet visible absorption spectrophotometry and optical rotation with comparison to standards ... /are/ methods for identifying levonorgestrel; potentiometric titration and ultra-violet absorption spectrophotometry are used to assay its purity. Levonorgestrel is identified in pharmaceutical preparations by ultra-violet absorption visible spectrophotometry and thin-layer chromatography
IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: https://monographs.iarc.fr/ENG/Classification/index.php, p. V72 592 (1999)
Analyte: levonorgestrel; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards
U.S. Pharmacopeia. The United States Pharmacopeia, USP 32/The National Formulary, NF 27; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p. 2774 (2009)
Analyte: levonorgestrel; matrix: chemical purity; procedure: infrared absorption spectrophotometry with comparison to standards
U.S. Pharmacopeia. The United States Pharmacopeia, USP 32/The National Formulary, NF 27; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p. 2774 (2009)

10 Safety and Hazards

10.1 Hazards Identification

10.1.1 GHS Classification

Pictogram(s)
Irritant
Health Hazard
Signal
Danger
GHS Hazard Statements

H302 (20.5%): Harmful if swallowed [Warning Acute toxicity, oral]

H312 (62.5%): Harmful in contact with skin [Warning Acute toxicity, dermal]

H332 (62.5%): Harmful if inhaled [Warning Acute toxicity, inhalation]

H351 (97.7%): Suspected of causing cancer [Warning Carcinogenicity]

H360 (95.5%): May damage fertility or the unborn child [Danger Reproductive toxicity]

H362 (30.7%): May cause harm to breast-fed children [Reproductive toxicity, effects on or via lactation]

Precautionary Statement Codes

P203, P260, P261, P263, P264, P270, P271, P280, P301+P317, P302+P352, P304+P340, P317, P318, P321, P330, P362+P364, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 88 reports by companies from 10 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

10.1.2 Hazard Classes and Categories

Acute Tox. 4 (20.5%)

Acute Tox. 4 (62.5%)

Acute Tox. 4 (62.5%)

Carc. 2 (97.7%)

Repr. 1A (95.5%)

Lact. (30.7%)

10.2 Accidental Release Measures

10.2.1 Disposal Methods

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.
SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

10.3 Handling and Storage

10.3.1 Storage Conditions

Store levonorgestrel tablets at 20 to 25 °C (68 to 77 °F)
US Natl Inst Health; DailyMed. Current Medication Information for NEXT CHOICE (levonorgestrel) tablet (December 2009). Available from, as of February 5, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=14292
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. The system is supplied as a sterile device and should not be resterilized. The device should not be used if the inner package is damaged or has been opened.
American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3122
Estrogen-progestin combinations generally should be stored at room temperature in a well-closed container, unless otherwise specified by the manufacturer. Commercially available oral contraceptives are provided in mnemonic (memory-aid) dispensing packages which are exempted from the child-safety packaging requirements of the US Poison Prevention Packaging Act of 1970.
American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3117

10.4 Regulatory Information

California Safe Cosmetics Program (CSCP) Reportable Ingredient

Hazard Traits - Reproductive Toxicity

Authoritative List - Prop 65

Report - regardless of intended function of ingredient in the product

10.4.1 FDA Requirements

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including levonorgestrel, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of March 17, 2011: https://www.accessdata.fda.gov/scripts/cder/ob/docs/queryai.cfm

10.5 Other Safety Information

Chemical Assessment

IMAP assessments - 18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-, (17.alpha.)-: Environment tier I assessment

IMAP assessments - 18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-, (17.alpha.)-: Human health tier I assessment

11 Toxicity

11.1 Toxicological Information

11.1.1 Drug Induced Liver Injury

Compound
levonorgestrel
DILI Annotation
No-DILI-Concern
Label Section
No match
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

11.1.2 Evidence for Carcinogenicity

Evaluation: There is inadequate evidence in humans for the carcinogenicity of progestogen-only contraceptives. There is sufficient evidence in experimental animals for the carcinogenicity of medroxyprogesterone acetate. Overall evaluation: Progestogen-only contraceptives are possibly carcinogenic to humans (Group 2B). /Progestogen-only contraceptives/
IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: https://monographs.iarc.fr/ENG/Classification/index.php, p. V72 385 (1999)

11.1.3 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

This record contains information specific to the levonorgestrel intrauterine device (IUD). Although nonhormonal methods are preferred during breastfeeding, progestin-only contraceptives such as levonorgestrel are considered the hormonal contraceptives of choice during lactation. Fair quality evidence indicates that levonorgestrel does not adversely affect the composition of milk, the growth and development of the infant or the milk supply. Expert opinion and a metanalysis hold that the risks of progestin-only contraceptive products usually are acceptable for nursing mothers at any time postpartum. There are no reports of adverse effects in breastfed infants with maternal use of progestin-only contraceptives. Low quality evidence indicates that there may be no difference in breastfeeding rates at 6 months between immediate and delayed insertion of progestin-releasing IUDs. Some evidence indicates that progestin-only contraceptives may offer protection against bone mineral density loss during lactation, or at least do not exacerbate it.

The World Health Association recommends that progestin-only intrauterine devices (IUDs) can be inserted before 48 hours postpartum and after 4 weeks postpartum, but should not be inserted between 48 hours and 4 weeks postpartum. Other guidelines and product labeling consider delayed postpartum insertion acceptable if immediate insertion is not feasible. Four small, randomized studies on this point differed in their outcomes. Three found that early insertion did not adversely affect breastfeeding, and the other found that immediate IUD insertion markedly reduced the breastfeeding rate at 6 months postpartum. A meta-analysis found that the risk of expulsion was no greater in breastfeeding mothers. More recent prospective studies found an increase in the risk of expulsion of intrauterine devices with breastfeeding, while a large retrospective study found a 29% lower risk of expulsion in breastfeeding women. The American College of Obstetrics and Gynecology recommends that women be counseled that immediate postpartum insertion may have a higher expulsion rate than later insertion.

◉ Effects in Breastfed Infants

One study found serum thyroid stimulating hormone levels to be lower in the infants exposed to levonorgestrel than in control infants.

IUDs that released levonorgestrel were inserted 6 weeks after delivery. IUDs released 10 mcg per day (n = 30) or 30 mcg per day (n = 40); copper-releasing IUDs (n = 40) were used as controls. No differences were seen in infant height, weight, development, respiratory infections or blood chemistries up to 12 months of age between the levonorgestrel and copper IUD groups.

Three hundred twenty lactating women were randomized to either an IUD containing levonorgestrel (Mirena; n = 163) or the copper-containing IUD Cu T380A group (n = 157). Follow-up of infants for 1 year found no differences in growth and development or in duration of breastfeeding.

◉ Effects on Lactation and Breastmilk

IUDs releasing levonorgestrel were inserted 6 weeks after delivery. IUDs released 10 mcg per day (n = 30) or 30 mcg per day (n = 40); copper-releasing IUDs (n = 40) were used as controls. The rate of breastfeeding discontinuation was higher with the levonorgestrel groups than in the copper IUD group at 75 days, but not at other times.

In a small prospective study, forty-six women were randomized to have an IUD containing levonorgestrel (Mirena) inserted either within 10 minutes after placental delivery (n = 15), between 10 minutes and 48 hours after placental delivery (n = 15), or after 6 weeks postpartum (n = 16). At 6 months postpartum, no statistical difference in the rates of continued breastfeeding (extent not stated) was found among the groups.

Women who gave birth were offered contraception with a levonorgestrel-containing IUD and randomized to have the IUD placed immediately following delivery (n = 46) or at 6 to 8 weeks postpartum (n = 50). Women randomized to later IUD insertion were more likely to be nursing at 6 months postpartum (24% vs 6%) and tended to have a longer median duration of exclusive breastfeeding.

A noninferiority trial compared breastfeeding in women who received a levonorgestrel IUD (product and dose not specified) immediately postpartum (n = 132) or at 8 weeks postpartum (n = 127). At 8 weeks, women who received the IUD immediately postpartum had a 5% lower rate of any breastfeeding (79% vs 84%), which fell withing the predetermined 15% noninferiority margin. Exclusive breastfeeding was slightly lower at 8 weeks in the immediate group (33% vs 40%), but the difference was not statistically significant. The time to lactogenesis in the immediate group was noninferior to that of the delayed group (65.3 vs 63.6 hours). Twenty-four device expulsions occurred in the immediate group compared to 2 in the delayed group (19% vs 2%), which was statistically significant.

◉ Summary of Use during Lactation

This record contains information specific to the levonorgestrel implant, which is not available in the United States. Although nonhormonal methods are preferred during breastfeeding, progestin-only contraceptives such as levonorgestrel are considered the hormonal contraceptives of choice during lactation. Fair quality evidence indicates that levonorgestrel does not adversely affect the composition of milk, the growth and development of the infant. Expert opinion and a metanalysis hold that the risks of progestin-only contraceptive products usually are acceptable for nursing mothers at any time postpartum. Limited, low quality evidence indicates that there is no difference in breastfeeding rates at 6 and 12 months between immediate and delayed insertion of progestin-containing contraceptive implants. Some evidence indicates that progestin-only contraceptives may offer protection against bone mineral density loss during lactation, or at least do not exacerbate it.

◉ Effects in Breastfed Infants

Numerous studies have found no systematic differences in growth, development or illness rates between the infants of mothers who received Norplant as a contraceptive and those of other mothers receiving either no contraception or nonhormonal contraception. One study found serum thyroid stimulating hormone levels to be lower in the infants exposed to levonorgestrel than in control infants.

Ten women received Norplant-2 beginning at 4 weeks postpartum. Mothers collected 4-hour urine samples daily from weeks 4 to 11 postpartum from their infants. Urine samples were analyzed for follicle-stimulating hormone, luteinizing hormone and testosterone. No difference was found in these levels when compared to those of infants whose mothers were taking either no contraception or an oral progestin-only contraceptive containing 30 mcg of levonorgestrel.

Multicenter, nonrandomized studies followed infants whose mothers received levonorgestrel contraception during breastfeeding, either as oral tablets of 37.5 mcg daily (n = 246) or as Norplant (n = 453). No adverse effects on infant growth through the first year were found in comparison to standard measurements. In a continuation study, infants from these studies who were exposed to levonorgestrel via Norplant (total n = 220) were followed up to 6 years of age. Infants were fully breastfed for an average of 7.8 months and were breastfed at least once daily for an average of 16.5 months. No differences in growth, diseases, surgery or hospitalizations were found from years 2 through 6 between infants whose mothers used levonorgestrel implants or Copper T IUD. An increase in skin conditions occurred in the levonorgestrel group and an increase in urogenital conditions occurred in the Copper T group.

◉ Effects on Lactation and Breastmilk

Numerous studies of varying size and quality have found that the use of levonorgestrel implants (Norplant or Norplant-2) as a contraceptive beginning at 7 days postpartum or later either has no clinically important negative effect on the quality of breastmilk and results in either no effect or an increase in the milk supply and duration of lactation.

In a nonrandomized study, 100 women who received Norplant implants at an average of day 55 postpartum were compared to 100 women receiving a postpartum IUD. No differences were found between the control and Norplant groups in the number of women nursing at days 10 and 20 and months 1 to 12 postinsertion except a slight decrease in the number of mothers using Norplant who were exclusively breastfeeding at 12 months. No difference since the time of weaning was noted between the groups.

A secondary analysis of a study in Uganda examined 96 postpartum women randomized to receive a 2-rod levonorgestrel implant (Jadelle, Bayer AG, Berlin) either within 5 days of birth (n = 55) or at 6 to 8 weeks postpartum (n = 42). No differences were found between the groups in infant growth from birth to 6 months, time to lactogenesis II, or proportion of mothers breastfeeding at 3 and 6 months.

A study in Malawi compared the breastfeeding rates between women who received an etonogestrel (n = 28) or levonorgestrel (n= 112) implant immediately postpartum. Mothers chose the method and were followed for 2 years postpartum. Most women breastfed for 2 years. No difference was seen in the exclusive breastfeeding rate at 6 months between the groups nor in the continuation of breastfeeding to 2 years.

◉ Summary of Use during Lactation

This record contains information specific to oral levonorgestrel used alone for contraception. Those with an interest in a combination oral contraceptive should consult the record entitled, Contraceptives, Oral, Combined.

Although nonhormonal methods are preferred during breastfeeding, progestin-only contraceptives such as levonorgestrel are considered the hormonal contraceptives of choice during lactation. Fair quality evidence indicates that levonorgestrel does not adversely affect the composition of milk, the growth and development of the infant or the milk supply. Expert opinion holds that the risks of progestin-only contraceptive products usually are acceptable for nursing mothers at any time postpartum. Some evidence indicates that progestin-only contraceptives may offer protection against bone mineral density loss during lactation, or at least do not exacerbate it. A large percentage of women who planned to breastfeed discontinued oral progestin-only contraceptives by 3 months postpartum and progestin-only contraceptives often result in rapid repeat pregnancy. Postcoital levonorgestrel appears to have no long-term adverse effects on breastfeeding or the infant.

◉ Effects in Breastfed Infants

One study found serum thyroid stimulating hormone levels to be lower in the infants exposed to levonorgestrel than in control infants.

A nonrandomized trial compared 250 breastfed infants whose mothers received 30 mcg daily of oral levonorgestrel initiated 7 days postpartum to 250 infants whose mothers received nonhormonal contraception. No differences in height and weight gain were seen during the 9-month study period between the 2 groups.

Multicenter, nonrandomized studies followed infants whose mothers received levonorgestrel contraception during breastfeeding, either as oral tablets of 37.5 mcg daily (n = 246) or as Norplant (n = 453). No adverse effects on infant growth through the first year were found in comparison to standard measurements.

In a cohort study of 71 nursing women who took levonorgestrel as a postcoital contraceptive, none noticed any adverse effect in their infants.

In a cohort study, breastfed infants of women (n = 100) who used at least one dose of levonorgestrel as a postcoital contraceptive in addition to the lactational-amenorrhea method (LAM) of birth control were compared to infants whose mothers used LAM only (n = 100). No statistically significant differences were found between the groups in weight, length, head circumference, chest circumference, and mid-arm circumference at 3 and 6 months postpartum, nor in the Denver Developmental Screening Test results at 6 months postpartum.

◉ Effects on Lactation and Breastmilk

Among a cohort study of 71 women who took levonorgestrel as a postcoital contraceptive during nursing, none reported any obvious decrease in milk supply after the drug was used.

A study of 1158 postpartum randomized women using the lactational amenorrhea method (LAM) for birth control randomized to be given levonorgestrel as a postcoital contraceptive or given nothing. No difference in the duration of breastfeeding was found between women who used the levonorgestrel and those who did not.

In a nonrandomized, nonblinded study comparing women who were breastfeeding at discharge, 102 postpartum women received depot medroxyprogesterone acetate (dosage not stated) in the early postpartum period (average 51.9 hours postpartum; range 6.25 to 132 hours), 181 received another progestin-only contraceptive and 138 used nonhormonal contraception. No differences in breastfeeding rates were seen at 2 and 6 weeks, but women receiving any hormonal contraceptive were breastfeeding at a lower rate (72.1% vs 77.6%) at 4 weeks postpartum. The authors concluded that progestin-only contraception initiated in the early postpartum period had no adverse effects on breastfeeding rates.

A study analyzed data from a prospective cohort study of U.S. women from May 2005 through June 2007. Women were followed from the third trimester of pregnancy throughout the first year postpartum. Data from the subset of women who professed that intended to breastfeed for 3 months or longer postpartum during their third trimester of pregnancy and who were using a contraceptive at 3 months postpartum were analyzed (n = 1349). Women who intended to breastfeed for at least 4 months and were taking a progestin-only oral contraceptive, such as levonorgestrel, were 3.15 times more likely to be breastfeeding (exclusive or nonexclusive) at 4 months than women who used a nonhormonal contraceptive. Women who said they would breastfeed for 3 to 4 months had 4-month breastfeeding rates equivalent to those using a nonhormonal contraceptive. These rates were much higher than those of women who were taking an estrogen-containing, combined oral contraceptive.

In a cohort study, women (n = 100) who used at least one dose of levonorgestrel as a postcoital contraceptive in addition to the lactational-amenorrhea method (LAM) of birth control were compared to mothers used LAM only (n = 100). No difference was found in the mothers' subjective opinions of their milk supplies.

11.1.4 Interactions

Significant changes (increase or decrease) in the plasma levels of the progestin have been noted in some cases of coadministration with HIV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors.
US Natl Inst Health; DailyMed. Current Medication Information for NEXT CHOICE (levonorgestrel) tablet (December 2009). Available from, as of February 5, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=14292
Contraceptive effectiveness may be reduced when hormonal contraceptives are co-administered with antibiotics, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids. This could result in unintended pregnancy or breakthrough bleeding. Examples include rifampin, rifabutin, barbiturates, primidone, phenylbutazone, phenytoin, dexamethasone, carbamazepine, felbamate, oxcarbazepine, topiramate, griseofulvin, and modafinil. In such cases a back-up nonhormonal method of birth control should be considered.
US Natl Inst Health; DailyMed. Current Medication Information for AVIANE (levonorgestrel and ethinyl estradiol) kit (September 2009). Available from, as of February 5, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=14957
Several cases of contraceptive failure and breakthrough bleeding have been reported in the literature with concomitant administration of antibiotics such as ampicillin and other penicillins, and tetracyclines. However, clinical pharmacology studies investigating drug interactions between combined oral contraceptives and these antibiotics have reported inconsistent results.
US Natl Inst Health; DailyMed. Current Medication Information for AVIANE (levonorgestrel and ethinyl estradiol) kit (September 2009). Available from, as of February 5, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=14957
Herbal products containing St. John's Wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding.
US Natl Inst Health; DailyMed. Current Medication Information for AVIANE (levonorgestrel and ethinyl estradiol) kit (September 2009). Available from, as of February 5, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=14957
For more Interactions (Complete) data for LEVONORGESTREL (8 total), please visit the HSDB record page.

11.1.5 Antidote and Emergency Treatment

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160-1

11.1.6 Human Toxicity Excerpts

/CASE REPORTS/ ...This case describes a 39-year-old multiparous patient who visited the gynecology outpatient department at a district general hospital with a history of heavy, prolonged periods for 1 year. Hysteroscopy and biopsy specimen revealed benign nonsecretory endometrium and a levonorgestrel-releasing IUS was inserted. The patient visited again 4 years later with an 8-month history of prolonged bleeding. Endometrial biopsy specimen confirmed well-differentiated endometrioid adenocarcinoma. This is the first case report, to our knowledge, where hysteroscopy was performed before levonorgestrel-releasing IUS insertion with conclusive evidence of initial negative malignancy followed by development of endometrial cancer 4 years after insertion. This case raises the question of the safety of levonorgestrel-releasing IUS for the prevention and treatment of endometrial hyperplasia and carcinoma.
Flemming R et al; J Minim Invasive Gynecol 15 (6): 771-3 (2008)
/CASE REPORTS/ ... A resident at the Family Practice Clinic of the University of California, Davis, inserted a levonorgestrel implant (Norplant system) into a 25-year-old African-American woman as she requested. The resident used the 7-step method recommended by the manufacturer to insert the implant. The woman went to the emergency department 24 hours after the insertion because the insertion site had diffuse redness, swelling, and blistering. Physicians prescribed 500 mg dicloxacillin every 6 hours for 10 days to treat suspected cellulitis. She returned to the clinic 1 week later, at which time the redness and blisters had disappeared. No drainage, fluctuance, or tenderness remained at the insertion site, which was clean. At her 3 month follow-up appointment, the insertion site itched constantly. The physician noted a fan-shaped area of hyperpigmentation at the insertion site. The physician prescribed 0.1% triamcinolone cream and told her to return for follow-up care. She returned in 3 months with complaints of itching and pain at the site. The physician noticed a fan-shaped keloid over the implant site and at the wound site. The patient asked for the implants to be removed. The physician did not encounter any difficulties in removing the 6 capsules and injected aqueous triamcinolone acetate into the keloid. Her mother had also experienced keloid formation. Resolution of the keloid at the implant site was noted at her 6-month follow-up visit. Based on a review of the literature, the cause of blister formation and subsequent keloid formation was likely multifactorial. The risk for keloid formation is highest in people with deeper skin pigmentation regardless of race, a family history of keloid, own history of keloid, and ethnic background. Patients should be counseled about the possibility of skin reactions such as keloid to implants.
Nuovo J, Sweha A; J Am Board Fam Pract 7 (2): 152-4 (1994)
/CASE REPORTS/ A 29-year-old woman presented to the gynecology outpatient clinic with abdominal discomfort following the insertion of a levonorgestrel intrauterine system (LNG-IUS). It was noted that although the patient remained amenorrheic since the insertion, there was a persistent left iliac fossa discomfort, which was constant in nature and not made worse by intercourse. On examination, there was a vague tenderness in the left iliac fossa, and a transvaginal ultrasound scan showed bright echoes outside the uterus suggestive of an extrauterine IUS. Thus, arrangements were made for an admission for hysteroscopy and laparoscopy, proceeding to laparotomy if required. Following the procedures, the patient reported disappearance of the discomfort, although the LNG-IUS had not yet been retrieved. X-ray revealed the device lying high in the abdomen and laparoscopy was conducted. The LNG-IUS itself was buried, but was easily retrieved with gentle counteraction on the omentum through a 5 mm laparoscopy portal. Overall, this case emphasizes the importance of an X-ray as well as an ultrasound investigation in such cases.
Bobrow C et al; Br J Fam Plann 26 (2): 105-6 (2000)
/CASE REPORTS/ The case report describes a relapse of Crohn's disease in a woman soon after the fitting of a levonorgestrel intrauterine system (IUS). Whilst the published evidence on the effects of levonorgestrel IUS in patients with pre-existing inflammatory bowel disease is limited, reports to date suggest that caution should be exercised when considering fitting an IUS in such women, even if there appears to be much to gain from an expected reduction in menorrhagia.
Wakeman J; J Fam Plann Reprod Health Care 29 (3): 154 (2003)
For more Human Toxicity Excerpts (Complete) data for LEVONORGESTREL (33 total), please visit the HSDB record page.

11.1.7 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ There was no increase in tumorigenicity following administration of levonorgestrel to rats for 2 years at approximately 5 ug/day, to dogs for 7 years at up to 0.125 mg/kg/day, or to rhesus monkeys for 10 years at up to 250 ug/kg/day.
US Natl Inst Health; DailyMed. Current Medication Information for NEXT CHOICE (levonorgestrel) tablet (December 2009). Available from, as of February 5, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=14292
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In a 7 year dog study, administration of levonorgestrel at 0.5 mg/kg/day did increase the number of mammary adenomas in treated dogs compared to controls. There were no malignancies.
US Natl Inst Health; DailyMed. Current Medication Information for NEXT CHOICE (levonorgestrel) tablet (December 2009). Available from, as of February 5, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=14292
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Groups of 30 Syria golden Hamsters, five weeks of age, received four weekly subcutaneous injections of N-nitrobis(2-oxypropyl)amine (NBOPA) at the dose of 10 mg/kg bw to initiate renal tumorigenesis and the received either control diet or a diet containing 10 mg/kg diet (ppm) levonorgestrel for 27 weeks. A third group of animals was not treated with nitrosamine but was fed the diet containing levonorgestrel. Levonorgestrel alone did not cause renal tumors or dysplasia. Initiation with NBOPA caused nephroblastoma in 1/21 animals and 469 dysplastic tubules. Levonorgestrel did not significantly enhance the incidence of renal tumors in initiated animals (2/27 nephroblastomas and 2/27 renal adenomas) or increase the total number of dysplastic tubules.
IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: https://monographs.iarc.fr/ENG/Classification/index.php, p. V72 370 (1999)
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ One hundred and fourteen rabbits, approximately 2.5 years old, were subjected to laparotomy and cross-sectional endomyometrial biopsy. Randomly selected rabbits then received a levonorgestrel-containing or an inert intrauterine implant in the right uterine horn. The implants consisted of a 0.3 x 2 cm core of either polydimethylsiloxane or 50% polydimethylsiloxane and 50% levonorgestrel. The rabbits then underwent a second cross-sectional endomometrial biopsy at six, 12 and 24 months. Of the 55 rabbits that received levonorgestrel and the 53 rabbits that received inert implants, 29 given levonorgestrel and 33 given inert implants survived 24 months. After 24 months, the incidence of endometrial carcinomas in rabbits receiving levonorgestrel (17%) was significantly lower (p < 0.05) than that developing spontaneously in rabbits receiving the inert implant (42%).
IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: https://monographs.iarc.fr/ENG/Classification/index.php, p. V72 369 (1999)
/GENOTOXICITY/ Levonorgestrel was not found to be mutagenic or genotoxic in the Ames Assay, in vitro mammalian culture assays utilizing mouse lymphoma cells and Chinese hamster ovary cells, and in an in vivo micronucleus assay in mice.
US Natl Inst Health; DailyMed. Current Medication Information for NEXT CHOICE (levonorgestrel) tablet (December 2009). Available from, as of February 5, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=14292

11.1.8 Ecotoxicity Excerpts

/AQUATIC SPECIES/ ...The effects of two progestins currently marketed in contraceptive formulations, levonorgestrel (LNG) and drospirenone (DRSP), were investigated in adult fathead minnows (Pimephales promelas) following an OECD 21-day fish reproduction screening assay draft protocol with additional end points. Levonorgestrel was tested at measured concentrations of 0.8, 3.3, and 29.6 ng/L, and DRSP at concentrations of 0.66, 6.5, and 70 uL. Both tested progestins caused an inhibition of reproduction. For LNG, this occurred at concentrations of 2:0.8 ng/L, no no-observed-effect concentration (NOEC) could be defined. Higher concentrations resulted in masculinization of females with de novo synthesis of nuptial tubercles. Drospirenone treatment, however, affected the reproductive success of fathead minnow at concentrations of 6.5 uL and higher with a clear dose-response relationship and a NOEC of 0.66 uL, which is above environmentally relevant concentrations.
Zeilinger J et al; Environ Toxicol Chem 28 (12): 2663-70 (2009)

11.1.9 Populations at Special Risk

Oral contraceptives have been reported to produce harmful ocular effects in myopic women. In women who developed myopia at or near puberty and in whom myopia became stable in adulthood, the drugs have reportedly increased the refractive error 2- to 3-fold, usually after 6 months of use. In women who are myopic and have considerable astigmatism, oral contraceptives may produce marked changes in the astigmatic error, possibly leading to frank keratoconus. In addition, oral contraceptives may produce a rapid advancement of the ocular disorder in patients with a family history of marked myopic astigmatism or keratoconus. Contact lens wearers receiving estrogen-progestin contraceptives may have more difficulties with their contact lenses than do nonusers who wear contact lenses. Contact lens wearers who develop visual disturbances or changes in lens tolerance during estrogen-progestin contraceptive use should be assessed by an ophthalmologist; temporary or permanent cessation of contact lens wear should be considered. /Estrogen-Progestin Combination/
American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3112
Mental depression may occur in women receiving oral contraceptives. In a few cases, mental depression has been severe and has led to suicidal behavior. Mental depression appears to occur most frequently in patients with a history of depression, including premenstrual depression; however, relief of premenstrual tension occurs in some women. Patients with a history of mental depression should be observed carefully and the estrogen-progestin contraceptive discontinued if severe depression recurs during use. /Estrogen-Progestin Combination/
American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3111
Women requiring chronic corticosteroid therapy or insulin for diabetes mellitus should be carefully monitored for development of infection. The levonorgestrel-releasing intrauterine system should be used with caution in women who have a coagulopathy or are receiving anticoagulants. 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.
American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3121

11.1.10 Protein Binding

The protein binding of levonorgestrel ranges from 97.5-99%, and it is mainly bound to sex hormone-binding globulin (SHBG). Levonorgestrel is also bound to albumin. The prescribing information for the implanted levonorgestrel indicates that the concentration of sex hormone-binding globulin (SHBG) is reduced in the span of a few days after levonorgestrel administration, decreasing the levels of the drug.

11.2 Ecological Information

11.2.1 Environmental Fate / Exposure Summary

Levonorgestrel's production and use as an oral contraceptive component may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 3.92X10-10 mm Hg at 25 °C indicates levonorgestrel will exist solely in the particulate phase in the atmosphere. Particulate-phase levonorgestrel will be removed from the atmosphere by wet or dry deposition. Levonorgestrel contains chromophores that absorb light at >290 nm and therefore may be susceptible to direct photolysis by sunlight. If released to soil, levonorgestrel is expected to have no mobility based upon an estimated Koc of 8,100. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 7.7X10-10 atm-cu m/mole. Biodegradation data were not available. If released into water, levonorgestrel is expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 92 suggests the potential for bioconcentration in aquatic organisms is moderate. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. Occupational exposure to levonorgestrel may occur through inhalation and dermal contact with this compound at workplaces where levonorgestrel is produced or used. Exposure to levonorgestrel via ingestion will occur when administered drugs containing this compound. Monitoring data indicate that the general population may be exposed to levonorgestrel at well below the therapeutic dose via ingestion of drinking water. (SRC)

11.2.2 Artificial Pollution Sources

Levonorgestrel's production and use as an oral contraceptive component(1) may result in its release to the environment through various waste streams(SRC).
(1) IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). V72: 592 (1999). Available from, as of Jan 31, 2011: https://monographs.iarc.fr/index.php

11.2.3 Environmental Fate

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 8,100(SRC), determined from a structure estimation method(2), indicates that levonorgestrel is expected to be immobile in soil(SRC). Volatilization of levonorgestrel from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 7.7X10-10 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Levonorgestrel is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.92X10-10 mm Hg at 25 °C(SRC), determined from a fragment constant method(4). Biodegradation data in soil were not available(SRC, 2011).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992)
(3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(4) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 8,100(SRC), determined from a structure estimation method(2), indicates that levonorgestrel is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 7.7X10-10 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 92(SRC), from an estimated log Kow of 3.48(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Biodegradation data in water were not available(SRC, 2011).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992)
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)
(4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(5) Franke C et al; Chemosphere 29: 1501-14 (1994)
(6) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995)
(7) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.0. Jan, 2009. Available from, as of DATE: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), levonorgestrel, which has an estimated vapor pressure of 3.9X10-10 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase levonorgestrel may be removed from the air by wet or dry deposition(SRC). Levonorgestrel contains chromophores that absorb light at <290 nm(3) and therefore may be susceptible to direct photolysis by sunlight(SRC).
(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988)
(2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 8-12 (1990)

11.2.4 Environmental Abiotic Degradation

Levonorgestrel is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Levonorgestrel contains chromophores that absorb light at <290 nm(1) and therefore may be susceptible to direct photolysis by sunlight(SRC).
(1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5, 8-12 (1990)

11.2.5 Environmental Bioconcentration

An estimated BCF of 92 was calculated in fish for levonorgestrel(SRC), using an estimated log Kow of 3.48(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate(SRC).
(1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.0. Jan, 2009. Available from, as of DATE: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(3) Franke C et al; Chemosphere 29: 1501-14 (1994)

11.2.6 Soil Adsorption / Mobility

Using a structure estimation method based on molecular connectivity indices(1), the Koc of levonorgestrel can be estimated to be 8,100(SRC). According to a classification scheme(2), this estimated Koc value suggests that levonorgestrel is expected to be immobile in soil.
(1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992)
(2) Swann RL et al; Res Rev 85: 17-28 (1983)

11.2.7 Volatilization from Water / Soil

The Henry's Law constant for levonorgestrel is estimated as 7.7X10-10 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that levonorgestrel is expected to be essentially nonvolatile from water and moist soil surfaces(2). Levonorgestrel is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.92X10-10 mm Hg(SRC), determined from a fragment constant method(3).
(1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)
(3) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)

11.2.8 Environmental Water Concentrations

While data specific to levonorgestrel were not located(SRC, 2011), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).
(1) Heberer T; Tox Lett 131: 5-17 (2002)
(2) Koplin DW et al; Environ Sci Toxicol 36: 1202-211 (2002)

11.2.9 Effluent Concentrations

Levonorgestrel was detected in effluent from the Eysines Sewage Treatment Plant (northern suburbs, Bordeaux, France) at mean concentrations of <5.0, <2.0, and <2.0 ng/L in July 2003, September 2003, and February 2004, respectively (detection limit = 5.0, 2.0, and 2.0, respectively)(1). The compound was tested for but not detected (detection limit = 2-100 ng/L) in effluent samples from sewage treatment plants in the vicinity of Barcelona, Spain, sampled from April to June, 1999(2).
(1) Labadie P, Budzinski H; Environ Sci Technol 39: 5113-5120 (2005)
(2) Sole M et al; Environ Sci Technol 34: 5076-5083 (2000)

11.2.10 Milk Concentrations

EXPERIMENTAL: ... Twelve healthy exclusively breastfeeding volunteers received 1.5 mg levonorgestrel (LNG). Women refrained from nursing for 72 hr after dosing and fed their infants with milk frozen beforehand. Serial blood and milk samples were collected for 120 hr and assayed for LNG and sex hormone binding globulin. LNG concentrations peaked in plasma and in milk 1-4 hr and 2-4 hr after dosing, respectively. Concentrations in milk (M) paralleled those in plasma (P) but were consistently lower (mean M:P ratio 0.28). Estimated infant exposure to LNG is 1.6 ug on the day of dosing (1 ug in the first 8 hr), 0.3 ug on the second day and 0.2 ug on the third day. Nursing mothers may need EC. These results suggest that to limit infant exposure to the period of maximum LNG excretion in milk, mothers should discontinue nursing for at least 8 hr, but not more than 24 hr, after EC.
Gainer E et al; Hum Reprod 22 (6): 1578-84 (2007)

11.2.11 Other Environmental Concentrations

Occupational exposure to levonorgestrel may occur through inhalation and dermal contact with this compound at workplaces where levonorgestrel is produced or used. Exposure to levonorgestrel via ingestion will occur when administered drugs containing this compound. Monitoring data indicate that the general population may be exposed to levonorgestrel at well below the therapeutic dose via ingestion of drinking water. (SRC)

12 Literature

12.1 Springer Nature References

13 Patents

13.1 FDA Orange Book Patents

FDA Orange Book Patents

14 Interactions and Pathways

14.1 Chemical-Target Interactions

14.2 Drug-Drug Interactions

14.3 Drug-Food Interactions

  • Take at the same time every day.
  • Take with or without food. The effect of food on absorption has not been evaluated.

15 Information Sources

  1. PubChem
  2. Australian Industrial Chemicals Introduction Scheme (AICIS)
    18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-, (17.alpha.)-
    https://services.industrialchemicals.gov.au/search-assessments/
  3. ChemIDplus
  4. DrugBank
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    https://www.drugbank.ca/legal/terms_of_use
  5. DTP/NCI
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  6. EPA DSSTox
  7. European Chemicals Agency (ECHA)
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    https://echa.europa.eu/web/guest/legal-notice
  8. FDA Global Substance Registration System (GSRS)
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  9. Hazardous Substances Data Bank (HSDB)
  10. California Safe Cosmetics Program (CSCP) Product Database
  11. DailyMed
  12. Drug Induced Liver Injury Rank (DILIrank) Dataset
    LICENSE
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  13. FDA Pharm Classes
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  14. NCI Thesaurus (NCIt)
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  15. European Medicines Agency (EMA)
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    https://www.ema.europa.eu/en/about-us/legal-notice
  16. Drugs and Lactation Database (LactMed)
  17. Drugs@FDA
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  18. FDA Orange Book
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  19. National Drug Code (NDC) Directory
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  20. Japan Chemical Substance Dictionary (Nikkaji)
  21. MassBank of North America (MoNA)
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    https://mona.fiehnlab.ucdavis.edu/documentation/license
  22. NLM RxNorm Terminology
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    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  23. Pharos
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  24. Springer Nature
  25. WHO Anatomical Therapeutic Chemical (ATC) Classification
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  26. WHO Model Lists of Essential Medicines
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  27. Wikipedia
CONTENTS