Levonorgestrel

G03A - Hormonal contraceptives for systemic use ATC G03AC03 Small molecule approved 1982 Oral Parenteral Topical Natural product

JFDA label: Mirena IUS

Mechanism of Action

Agonist of Progesterone receptor — Progesterone receptor agonist

Target	Action	Gene / class
Progesterone receptor efficacy	AGONIST	PGR

Indications

Approved

Emergency contraception

Contraindications

Source: Lexicomp

Known or suspected pregnancy Absolute
OTC labeling: When used for self-medication, do not use if you are already pregnant Absolute
do not use for regular birth control Absolute
hypersensitivity to levonorgestrel or any component of the formulation Absolute
undiagnosed vaginal bleeding It is not known if the same contraindications associated with long-term progestin-only contraceptives apply to the levonorgestrel emergency contraception dose regimens Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Nervous system disorders (3)

Very Common Fatigue

Common Dizziness · headache

Renal and urinary disorders (1)

Common Breast tenderness

Metabolism and nutrition disorders (2)

Very Common Hypermenorrhea

Common Suppressed menstruation

Gastrointestinal disorders (2)

Very Common abdominal pain · Nausea

Other (5)

Not Known Dysmenorrhea · irregular menses · oligomenorrhea · pelvic pain · vomiting

Dosing

Source: Lexicomp

Emergency contraception: Females: Oral: May be used at any time during menstrual cycle: Two-dose regimen: One 0.75 mg tablet as soon as possible within 72 hours of unprotected sexual intercourse; a second 0.75 mg tablet should be taken 12 hours after the first dose. Single-dose regimen: One 1.5 mg tablet as soon as possible within 72 hours of unprotected sexual intercourse. Note: Treatment for emergency contraception should begin as soon as possible; however, treatment is still moderately effective if used within 5 days and should be made available to women up to 5 days after unprotected or inadequately protected intercourse. When using the two-dose emergency contraceptive regimen, the second dose is equally effective if taken 12 to 24 hours after the first (ACOG, 2015).

Emergency contraception: Females: Refer to adult dosing. Not for use prior to menarche.

Not indicated for use in postmenopausal women.

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Warnings & Precautions

Source: Lexicomp

Bleeding irregularities

Spotting may occur following use; the possibility of pregnancy should be considered if menstruation is delayed for >7 days of the expected menstrual period (ACOG 2015).

Ectopic pregnancy

A history of ectopic pregnancy is not a contraindication for use as an emergency contraceptive (Curtis 2016b). The possibility of ectopic pregnancy should be considered in patients with lower abdominal pain, especially in association with missed periods or vaginal bleeding in women with prior amenorrhea (ACOG 2015). Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Other warnings/precautions:

Appropriate use

Not intended to be used for routine contraception and is not effective in terminating an existing pregnancy (ACOG 2015).

Body weight

Use as an emergency contraceptive may be less effective in women with a BMI ≥30 kg/m2 compared with women with a BMI ≤25 kg/m2; however, no safety concerns exist and the advantages of use generally outweigh potential risks (Curtis 2016b). The CDC recommends that obese women can generally use any type of contraceptive but suggests that levonorgestrel may be less efficacious in obese women compared to ulipristal acetate (Curtis 2016a).

Fertility

Barrier contraception is recommended immediately following emergency contraception (ACOG 2015; Curtis 2016a).

HIV infection protection

Emergency contraceptives do not protect against HIV infection or other sexually transmitted diseases (Curtis 2016a).

Pregnancy & Lactation

Pregnancy

Not for use in women confirmed to be pregnant. Adverse effects to the mother or fetus have not been observed following inadvertent exposure during pregnancy (Curtis 2016b). Levonorgestrel may be used as an emergency contraceptive in women with contraindications to conventional oral contraceptive agents (eg, cardiovascular disease, migraines, liver disease) (ACOG 2015; Curtis 2016b). A rapid return of fertility is expected following use for emergency contraception; routine contraceptive measures should be initiated or continued following use to ensure ongoing prevention of pregnancy. Any regular contraceptive method can be started immediately after levonorgestrel; however, a barrier method (or abstinence from sexual intercourse) is also needed for 7 days (ACOG 2015; Curtis 2016a).

Lactation

Following maternal use of the oral tablets or intrauterine device, levonorgestrel is found in breast milk and can be detected in the serum of nursing infants (Shikary 1987). In general, no adverse effects on the growth or development of the infant have been observed. Isolated cases of decreased milk production have been reported. Women who are breastfeeding may use levonorgestrel for emergency contraception (ACOG 2015; Curtis 2016b).

Monitoring

Clinical pearl	Evaluate for pregnancy, spontaneous abortion or ectopic pregnancy if normal (expected) menstrual period is delayed for ≥1 week following emergency contraception, or if lower abdominal pain or persistent irregular bleeding develops (ACOG 2015).

Chemistry & Properties

Formula	C21H28O2
Molecular weight	312.45 g/mol
CAS	797-63-7
PubChem CID	13109
InChIKey	`WWYNJERNGUHSAO-XUDSTZEESA-N`
logP	3.88
Polar surface area	37.3 Å²
H-bond acceptors / donors	2 / 1
Drug-likeness (QED)	0.75
Lipinski violations	0

SMILES

C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	2.791 h
Volume of distribution	2.037 L/kg
Protein binding	97.0%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP2B6	Inhibitor	—
CYP2C19	Inhibitor	—
CYP2C19	Substrate	—
CYP2C8	Inhibitor	—
CYP3A4	Substrate	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Acitretin	major
Bexarotene	major
Brigatinib	major
Carfilzomib	major
Dabrafenib	major
Encorafenib	major
Griseofulvin	major
Lumacaftor	major
Mycophenolic acid	major
Sugammadex	major
Tranexamic acid	major
Acarbose	moderate
Acetohexamide	moderate
Adalimumab	moderate
Albiglutide	moderate
Alefacept	moderate
Alogliptin	moderate
Aminoglutethimide	moderate
Aminophylline	moderate
Anakinra	moderate
Apalutamide	moderate
Aprepitant	moderate
Artemether	moderate
Asparaginase Escherichia coli	moderate
Canagliflozin	moderate
Canakinumab	moderate
Certolizumab pegol	moderate
Chlorpropamide	moderate
Cladribine	moderate
Clarithromycin	moderate
Clotrimazole	moderate
Cobicistat	moderate
Cyclosporine	moderate
Dapagliflozin	moderate
Dasatinib	moderate
Deferasirox	moderate
Dulaglutide	moderate
Elagolix	moderate
Emapalumab	moderate
Empagliflozin	moderate

Showing 40 of 100+.

Registered Products (5)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
NORDIOL TABS	Tablet 50 mcg, 250 mcg	21 tab	Arab Company for Medical & Agricultural Products	1.290
Microgynon Tab	Tablet 0.03 mg, 0.15 mg	21 tab	The Jordan Drugstore Co	1.320
Navela	Tablet 1.5 mg	1 tab	Nairoukh Drug Store	8.220
Jadelle	Implant 75 mg	2 implants	The Jordan Drugstore Co	43.350
Mirena IUS	Implant 52 mg	1 IUS	The Jordan Drugstore Co	92.440