Levonorgestrel

Levonorgestrel (LNG) is a synthetic progestational hormone used in hormonal contraceptives and as a component in hormone replacement therapy. It is the biologically active form of the racemic mixture norgestrel.

Tags
Approvals
WHO Essential Medicine WHO Prequalification US FDA-Approved
Related Compounds
Norgestrel
levonorgestrel

Identifiers

Abbreviation

LNG

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References

Names

  • USAN, INN: Levonorgestrel
  • 18-methylnorethisterone
  • 17α-ethynyl-18-methyl-19-nortestosterone
  • 17α-ethynyl-18-methylestr-4-en-17β-ol-3-one

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References

CASRN

797-63-7

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References

PubChem CID

13109

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ECHA InfoCard

  • 100.011.227
  • EC/List #: 212-349-8

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IUPHAR/BPS

2881

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UNII

5W7SIA7YZW

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KEGG Entry Number

D00950

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Wikipedia Entry Name

Levonorgestrel

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ChEBI ID

CHEBI:6443

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ChEMBL ID

CHEMBL1389

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ChemSpider ID

12560

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PDB

NOG

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Physical & Chemical Properties

Molecular Formula

C21H28O2

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References

Molecular Weight

312.45 g/mol

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References

Vapor Pressure

3.92 x 10-10 mm Hg at 25° C (estimated)

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Storage Conditions

20 to 25° C (68 to 77° F). Preserve in well-closed, light-resistant containers.

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References

  1. US Pharmacopoeia 40 (2017): Levonorgestrel.
  2. (View all citations for this reference)

Toxicology

GHS Hazard Code(s)

Class Category Code Description
Acute Dermal Toxicity 4 H312 Harmful in contact with skin
Acute Inhalation Toxicity 4 H332 Harmful if inhaled
Carcinogenicity 2 H351 Suspected of causing cancer if inhaled
Reproductive Toxicity 1A H360FD May damage fertility. May damage the unborn child
Reproductive Toxicity, Effects On or Via Lactation H362 May cause harm to breast-fed children
Acute Oral Toxicity 4 H302 Harmful if swallowed
Reproductive Toxicity 1B H360 May damage fertility or the unborn child

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Side Effects

SIDER: Haemorrhage, vulvovaginitis, amenorrhoea, abdominal pain, fatigue, nausea, menometrorrhagia, abdominal pain lower, asthenia, ovarian cyst, dizziness, breast tenderness, headache, seborrhoeic dermatitis.
AHFS: Reported in 5% or more of women: abdominal pain, leukorrhea, headache, vaginitis, back pain, breast pain, acne, depression, hypertension, upper respiratory infection, nausea, nervousness, dysmenorrhea, weight increase, skin disorder, decreased libido, abnormal Pap smear, sinusitis.

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Biochemistry & Pharmacology

Progesterone Receptor Activity

Agonist

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References

Androgen Receptor Activity

Agonist

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References

  1. Africander, D.; Verhoog, N.; Hapgood, J. P., Molecular mechanisms of steroid receptor-mediated actions by synthetic progestins used in HRT and contraception. Steroids 2011, 76 (7), 636-52.
  2. (View all citations for this reference)
  3. Kumar, N.; Fagart, J.; Liere, P.; Mitchell, S. J.; Knibb, A. R.; Petit-Topin, I.; Rame, M.; El-Etr, M.; Schumacher, M.; Lambert, J. J.; Rafestin-Oblin, M. E.; Sitruk-Ware, R., Nestorone(R) as a Novel Progestin for Nonoral Contraception: Structure-Activity Relationships and Brain Metabolism Studies. Endocrinology 2017, 158 (1), 170-182.
  4. (View all citations for this reference)
  5. Kuhl, H., Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric 2005, 8 Suppl 1, 3-63.
  6. (View all citations for this reference)
  7. Ruan, X.; Seeger, H.; Mueck, A. O., The pharmacology of nomegestrol acetate. Maturitas 2012, 71 (4), 345-53.
  8. (View all citations for this reference)
  9. Lello, S., Nomegestrol Acetate Pharmacology, Safety Profile and Therapeutic Efficacy. Drugs 2010, 70 (5), 541-559.
  10. (View all citations for this reference)

Estrogen Receptor Activity

Antagonist

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References

  1. Africander, D.; Verhoog, N.; Hapgood, J. P., Molecular mechanisms of steroid receptor-mediated actions by synthetic progestins used in HRT and contraception. Steroids 2011, 76 (7), 636-52.
  2. (View all citations for this reference)
  3. Ruan, X.; Seeger, H.; Mueck, A. O., The pharmacology of nomegestrol acetate. Maturitas 2012, 71 (4), 345-53.
  4. (View all citations for this reference)
  5. Lello, S., Nomegestrol Acetate Pharmacology, Safety Profile and Therapeutic Efficacy. Drugs 2010, 70 (5), 541-559.
  6. (View all citations for this reference)
  7. Bartsch, V., Gynaecological uses of dienogest alone and in combination with oestrogens. Journal of Medical Drug Reviews 2015, 5, 1-31.
  8. (View all citations for this reference)

Glucocorticoid Receptor Activity

Conflicting reports: not active (Ruan, Lello), weakly effective (Nath), active (Bartsch), binds to GR (Jordan), low affinity (Africander)

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References

  1. Africander, D.; Verhoog, N.; Hapgood, J. P., Molecular mechanisms of steroid receptor-mediated actions by synthetic progestins used in HRT and contraception. Steroids 2011, 76 (7), 636-52.
  2. (View all citations for this reference)
  3. Nath, A.; Sitruk-Ware, R., Different cardiovascular effects of progestins according to structure and activity. Climacteric 2009, 12, 96-101. (View all citations for this reference)
  4. Jordan A. Toxicology of progestogens of implantable contraceptives for women. Contraception. 2002; 65:3-8.
  5. (View all citations for this reference)
  6. Bartsch, V., Gynaecological uses of dienogest alone and in combination with oestrogens. Journal of Medical Drug Reviews 2015, 5, 1-31.
  7. (View all citations for this reference)
  8. Ruan, X.; Seeger, H.; Mueck, A. O., The pharmacology of nomegestrol acetate. Maturitas 2012, 71 (4), 345-53.
  9. (View all citations for this reference)
  10. Lello, S., Nomegestrol Acetate Pharmacology, Safety Profile and Therapeutic Efficacy. Drugs 2010, 70 (5), 541-559.
  11. (View all citations for this reference)

Mineralocorticoid Receptor Activity

Agonist with high relative binding affinity. Conflicting reports on antagonism: Ruan and Lello indicate not active, while Africander says some anti-mineralocorticoid activity in rat models.

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References

  1. Africander, D.; Verhoog, N.; Hapgood, J. P., Molecular mechanisms of steroid receptor-mediated actions by synthetic progestins used in HRT and contraception. Steroids 2011, 76 (7), 636-52.
  2. (View all citations for this reference)
  3. Ruan, X.; Seeger, H.; Mueck, A. O., The pharmacology of nomegestrol acetate. Maturitas 2012, 71 (4), 345-53.
  4. (View all citations for this reference)
  5. Lello, S., Nomegestrol Acetate Pharmacology, Safety Profile and Therapeutic Efficacy. Drugs 2010, 70 (5), 541-559.
  6. (View all citations for this reference)

Cmax

14.1 +/- 7.7 ng/mL (adult females, single dose of Plan B [0.75 mg levonorgestrel] administered in the morning
7.5 +/- 3.8 ng/mL (adolescent females, single dose of Plan B [0.75 mg levonorgestrel] administered in the evening)

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Tmax

1.6 +/- 0.7 h (adult females, single dose of Plan B [0.75 mg levonorgestrel] administered in the morning
1.5 +/- 0.7 h (adolescent females, single dose of Plan B [0.75 mg levonorgestrel] administered in the evening)

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Elimination Half-Life (t1/2)

36 +/- 13 h at steady-state (Toxnet)
28 +/- 6.4 h (Toxnet)
24.4 +/- 5.3 h (adult females, one table of Plan B [0.75 mg levonorgestrel])
22.2 +/- 6.8 h (adolescent females, one table of Plan B [0.75 mg levonorgestrel])

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Serum Protein Binding

47.5% bound to SHBG, 50% to serum albumin, 2.5% unbound

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References

  1. Schindler, A. E.; Campagnoli, C.; Druckmann, R.; Huber, J.; Pasqualini, J. R.; Schweppe, K. W.; Thijssen, J. H. H., Classification and pharmacology of progestins. Maturitas 2003, 46, 7-16.
  2. (View all citations for this reference)
  3. Plan B Drug Approval Package (View all citations for this reference)

Enzyme Interactions

Inhibits 3-oxo-5-alpha-steroid 4-dehydrogenase 1, CYP19A1

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Inhibition of Ovulation

0.05-0.1 mg/day

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References

  1. Rebar, R. W.; Zeserson, K., CHARACTERISTICS OF THE NEW PROGESTOGENS IN COMBINATION ORAL-CONTRACEPTIVES. Contraception 1991, 44 (1), 1-10.
  2. (View all citations for this reference)

Transformation of Endometrium

5-6 mg/cycle

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References

  1. Rebar, R. W.; Zeserson, K., CHARACTERISTICS OF THE NEW PROGESTOGENS IN COMBINATION ORAL-CONTRACEPTIVES. Contraception 1991, 44 (1), 1-10.
  2. (View all citations for this reference)

Menstrual Delay

0.25-1.0 mg/day

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References

  1. Rebar, R. W.; Zeserson, K., CHARACTERISTICS OF THE NEW PROGESTOGENS IN COMBINATION ORAL-CONTRACEPTIVES. Contraception 1991, 44 (1), 1-10.
  2. (View all citations for this reference)

Metabolites

Name
Structure
Notes
structure

Estrogenic activity. Significantly reduced progestational activity.

structure

Also present as glucuronide conjugate.

structure

Also present as sulfate and glucuronide conjugates.

structure

Also present as sulfate and glucuronide conjugates.

structure

Sulfate conjugate also present, as well as the sulfate conjugate of the 16α stereoisomer. Metabolite of both levonorgestrel and norgestrel.

Impurities

Name
Structure
CASRN
Other Names & Identifiers
structure

1260525-53-8

  • BP Levonorgestrel Impurity A
  • δ8(14)-levonorgestrel
  • 13-ethyl-17-hydroxy-18,19-dinor-17α-pregna-4,8(14)-dien-20-yn-3-one

structure

19914-67-1

  • BP Levonorgestrel Impurity B
  • 13-ethyl-17-hydroxy-18,19-dinor-17α-pregn-5(10)-en-20-yn-3-one

US FDA-Approved Products

Name
Formulation
Status
ANDA #

Prescription

018206

ETHINYL ESTRADIOL: 0.02 mg LEVONORGESTREL: 0.1 mg 28 oral tablets

Prescription

201088

ETHINYL ESTRADIOL: 0.03 mg, 0.01 mg LEVONORGESTREL: 0.15 mg, N/A Oral tablet

Prescription

206851

ETHINYL ESTRADIOL: 0.03 mg LEVONORGESTREL: 0.15 mg Oral tablet

Prescription

090716

LEVONORGESTREL: 1.5 mg Oral tablet

Over-the-counter

202635

WHO Essential Medicines

Name
Formulation
Two-rod implant, each rod containing 75 mg LEVONORGESTREL (150 mg total)
Intrauterine system with reservoir containing 52 mg of LEVONORGESTREL
LEVONORGESTREL: 30 μg, 750 μg (pack of two), 1.5 mg
Tablet
ETHINYL ESTRADIOL: 35 μg
LEVONORGESTREL: 1 mg
Tablet
ETHINYL ESTRADIOL: 30 μg
LEVONORGESTREL: 150 μg
Tablet

WHO Prequalified Medicines

WHO Reference #
Name
Applicant
Formulation
RH058 (a)
1.5 mg, tablet
RH057
0.03 mg, film-coated tablet
RH046
1.5 mg, tablet
RH042 (a)
ETHINYL ESTRADIOL: 0.03 mg
LEVONORGESTREL: 0.15 mg
Tablet
Placebo tablet: 0 mg
RH041 (a)
ETHINYL ESTRADIOL: 0.03 mg
LEVONORGESTREL: 0.15 mg
Tablet
Placebo Tablet: 0 mg