Levonorgestrel is a hormonal medication which is used in a number of birth control methods. In pill form, sold under the brand name Plan B among others, it is useful within 120 hours as emergency birth control. It becomes less effective the longer after sex and only works before pregnancy has occurred. It is also combined with an estrogen to make combined oral birth control pills. Within an intrauterine device (IUD), sold as Mirena among others, it is effective for long-term prevention of pregnancy. An implantable form of levonorgestrel is also available in some countries.
Common side effects include nausea, breast tenderness, headaches, and increased, decreased, or irregular menstrual bleeding. When used as a form of emergency contraception, if pregnancy occurs, there is no evidence its use harms the baby. It is safe to use during breastfeeding. Birth control that contains levonorgestrel will not change the risk of sexually transmitted infections. It is a progestin and has effects similar to those of the hormone progesterone. It works mostly by preventing ovulation and closing off the cervix to prevent the passage of sperm.
Levonorgestrel was first made in the 1960s and its use as a method of birth control began in the 1980s. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. It is available as a generic medication. The wholesale cost in the developing world costs between 0.23 and 1.65 USD for the dose required for emergency birth control. In the United States it is over the counter for all ages.
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Medical uses
Birth control pills
At low doses, levonorgestrel is used in monophasic and triphasic formulations of combined oral contraceptive pills, with available monophasic doses ranging from 100-250 µg, and triphasic doses of 50 µg/75 µg/125 µg. It is combined with the estrogen ethinylestradiol in these formulations.
At very low daily dose of 30 µg, levonorgestrel is used in some progestogen only pill formulations.
Emergency birth control
Levonorgestrel is used in emergency contraceptive pills (ECPs), both in a combined Yuzpe regimen which includes estrogen, and as a levonorgestrel-only method. The levonorgestrel-only method uses levonorgestrel 1.5 mg (as a single dose or as two 0.75 mg doses 12 hours apart) taken within 3 days of unprotected sex, with one study indicating that beginning as late as 120 hours (5 days) after intercourse could be effective.
The primary mechanism of action of levonorgestrel as a progestogen-only emergency contraceptive pill is, according to International Federation of Gynecology and Obstetrics (FIGO), to prevent fertilization by inhibition of ovulation and thickening of cervical mucus. FIGO has stated that: "review of the evidence suggests that LNG [levonorgestreol] ECPs cannot prevent implantation of a fertilized egg. Language on implantation should not be included in LNG ECP product labeling." In November 2013, the European Medicines Agency (EMA) approved a change to the label saying it cannot prevent implantation of a fertilized egg.
Other studies still find the evidence to be unclear. While it is unlikely that emergency contraception affects implantation it is impossible to completely exclude the possibility of post-fertilization effect.
In November 2013, the EMA also approved a change to the label for HRA Pharma's NorLevo saying: "In clinical trials, contraceptive efficacy was reduced in women weighing 75 kg [165 pounds] or more, and levonorgestrel was not effective in women who weighed more than 80 kg [176 pounds]." In November 2013 and January 2014, the FDA and the EMA said they were reviewing whether increased weight and body mass index (BMI) reduce the efficacy of emergency contraceptives.
Intrauterine device
Levonorgestrel is the active ingredient in a number of intrauterine devices including Mirena and Skyla.
Birth control implant
Levonorgestrel is the active ingredient in Norplant and Jadelle.
Hormone therapy
Levonorgestrel is combined with estradiol in the estrogen patch for menopausal hormone therapy.
Side effects
After intake of 1.5 mg levonorgestrel in clinical trials, very common side effects (reported by 10% or more) included: hives, dizziness, headache, nausea, abdominal pain, uterine pain, delayed menstruation, heavy menstruation, uterine bleeding, and fatigue; common side effects (reported by 1% to 10%) included diarrhea, vomiting, and painful menstruation; these side effects usually disappeared within 48 hours.
Interactions
If taken together with drugs that induce the CYP3A4 cytochrome P450 liver enzyme, levonorgestrel may be metabolized faster and may have lower effectiveness.
Pharmacology
Pharmacodynamics
Levonorgestrel is a progestogen; that is, an agonist of the progesterone receptor (PR), the main biological target of the progestogen sex hormone progesterone. It is also a weak agonist of the androgen receptor (AR), the main biological target of the androgen sex hormone testosterone. Levonorgestrel has no other hormonal activity of significance, including antiprogestogenic or antiandrogenic, estrogenic or antiestrogenic, glucocorticoid or antiglucocorticoid, or mineralocorticoid or antimineralocorticoid. Its in vitro relative binding affinities at human steroid hormone receptors are: 323% that of progesterone at the progesterone receptor, 58% that of testosterone at the androgen receptor, 17% that of aldosterone at the mineralocorticoid receptor, 7.5% that of cortisol at the glucocorticoid receptor, and less than 0.02% that of estradiol at the estrogen receptor.
Levonorgestrel is a weakly androgenic progestin and may cause androgenic side effects such as decreased sex hormone-binding globulin (SHBG) levels, decreased HDL cholesterol levels, weight gain, and acne. In combination with a potent estrogen like ethinylestradiol however, all contraceptives containing androgenic progestins are negligibly androgenic in clinical practice and can in fact be used to treat androgen-dependent conditions like acne and hirsutism. This is because ethinylestradiol causes a marked increase in SHBG levels and thereby decreases levels of free and hence bioactive testosterone, acting as a functional antiandrogen. Nonetheless, contraceptives containing progestins that are less androgenic increase SHBG levels to a greater relative extent and are more effective for such indications. Levonorgestrel is the most androgenic progestin that is used in contraceptives, and contraceptives containing levonorgestrel may not be as effective for such indications relative to those containing other progestins that are less androgenic.
Pharmacokinetics
The bioavailability of levonorgestrel is approximately 95%. The plasma protein binding of levonorgestrel is about 98%. It is bound 50% to albumin and 48% to sex hormone-binding globulin. Levonorgestrel is metabolized in the liver, via reduction, hydroxylation, and conjugation. 5?-Dihydrolevonorgestrel is produced as an active metabolite of levonorgestrel by 5?-reductase. The elimination half-life of levonorgestrel is 24 to 32 hours.
Chemistry
Levonorgestrel, also known as 17?-ethynyl-18-methyl-19-nortestosterone or as 17?-ethynyl-18-methylestr-4-en-17?-ol-3-one, is a synthetic estrane steroid and a derivative of testosterone. It is the C13? or levorotatory stereoisomer and enantiopure form of norgestrel, the C13? or dextrorotatory isomer being inactive. Levonorgestrel is more specifically a derivative of norethisterone (17?-ethynyl-19-nortestosterone) and is the parent compound of the gonane (18-methylestrane) subgroup of the 19-nortestosterone family of progestins.
History
Levonorgestrel was first introduced in 1968, as an oral contraceptive in combination with ethinylestradiol.
Society and culture
Generic names
Levonorgestrel is the generic name of the drug and its INN, USAN, USP, BAN, DCIT, and JAN, while lévonorgestrel is its DCF.
Brand names
Levonorgestrel is marketed alone or in combination with an estrogen (specifically ethinylestradiol, estradiol, or estradiol valerate under a multitude of brand names throughout the world, including Alesse, Altavera, Alysena, Amethia, Amethyst, Ashlyna, Aviane, Camrese, Chateal, Climara Pro, Daysee, Emerres, Enpresse, Erlibelle, Escapelle, Falmina, Introvale, Isteranda, Jadelle, Jaydess, Jolessa, Klimonorm, Kurvelo, Kyleena, Lessina, Levlen, Levodonna, Levonelle, Levonest, Levosert, Levora, Liletta, Loette, Logynon, LoSeasonique, Lutera, Lybrel, Marlissa, Microgynon, Microlut, Min-Ovral, Miranova, Mirena, My Way, Myzilra, Next Choice, Nordette, Norgeston, NorLevo, Norplant, Option 2, Orsythia, Ovima, Ovranette, Plan B, Plan B One-Step, Portia, Postinor, Postinor-2, Ramonna, Rigevidon, Quartette, Quasense, Seasonale, Seasonique, Skyla, Sronyx, Tri-Levlen, Trinordiol, Triphasil, Triquilar, Tri-Regol, Trivora, and Upostelle, among many others. These formulations are used as emergency contraceptives, normal contraceptives, or in menopausal hormone therapy for the treatment of menopausal symptoms.
As an emergency contraceptive, levonorgestrel is often referred to colloquially as the "morning-after pill".
Availability
Levonorgestrel is very widely marketed throughout the world and is available in almost every country.
Over-the-counter
In 2013, the FDA approved Plan B One-Step for sale over-the-counter without a prescription or age restriction.
Indian Health Services
A policy update in 2015 required all Indian Health Services-run pharmacies, clinics, and emergency departments to have Plan B One-Step in stock, to distribute it to any woman (or her representative) who asked for it without a prescription, age verification, registration or any other requirement, to provide orientation training to all staff regarding the medication, to provide unbiased and medically accurate information about emergency contraception, and to make someone available at all times to distribute the pill in case the primary staffer objected to providing it on religious or moral grounds.
Source of the article : Wikipedia
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