Levonorgestrel is a hormonal medication used in a number of birth control methods. It is combined with an estrogen to make combination birth control pills. As an emergency birth control, sold under the brand names Plan B One-Step and Julie, among others, it is useful within 72 hours of unprotected sex. The more time that has passed since sex, the less effective the medication becomes. Levonorgestrel works by preventing or delaying ovulation so an egg cannot be released. The dosage used for emergency contraception is ineffective when ovulation has already occurred, and has been found to have no effect on implantation. It decreases the chances of pregnancy by 57–93%. In an intrauterine device (IUD), such as Mirena among others, it is effective for the long-term prevention of pregnancy. A levonorgestrel-releasing implant is also available in some countries.
Common side effects include nausea, breast tenderness, headaches, and increased, decreased, or irregular menstrual bleeding. When used as an emergency contraceptive, if pregnancy occurs, there is no evidence that its use harms the fetus. 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 primarily by preventing ovulation and closing off the cervix to prevent the passage of sperm.
Levonorgestrel was patented in 1960 and introduced for medical use together with ethinylestradiol in 1970. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication. In the United States, levonorgestrel-containing emergency contraceptives are available over the counter (OTC) for all ages. In 2020, it was the 323rd most commonly prescribed medication in the United States, with more than 800thousand prescriptions.
Medical uses
Birth control
At low doses, levonorgestrel is used in monophasic and triphasic formulations of combined oral contraceptive pills, with available monophasic doses ranging from 100 to 250 μg, and triphasic doses of 50 μg, 75 μg, and 125 μg. It is combined with the estrogen ethinylestradiol in these formulations. In addition to the single-dose emergency contraceptive, Cipla and later Piramal marketed i-pill Daily, a 21‑tablet combined daily oral contraceptive intended for regular birth control.
At very low daily dose of 30 μg, levonorgestrel is used in some progestogen-only pill formulations.
Levonorgestrel is the active ingredient in a number of intrauterine devices including Mirena and Skyla. It is also the active ingredient in the birth control implants Norplant and Jadelle.
One of the more common forms of contraception that contains only levonorgestrel is an IUD. One IUD, the Mirena, is a small hollow cylinder containing levonorgestrel and polydimethylsiloxane and covered with a release rate-controlling membrane.
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 three days of unprotected sex. One study indicated that beginning as late as 120 hours (5 days) after intercourse could be effective. However, taking more than one dose of emergency contraception does not increase the chance of pregnancy not happening. Planned Parenthood asserts "Taking the morning-after pill (also known as emergency contraception) multiple times doesn't change its effectiveness, and won't cause any long-term side effects."
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. p. 121:Mechanism of actionCopper-releasing IUCsWhen used as a regular or emergency method of contraception, copper-releasing IUCs act primarily to prevent fertilization. Emergency insertion of a copper IUC is significantly more effective than the use of ECPs, reducing the risk of pregnancy following unprotected intercourse by more than 99%.2,3 This very high level of effectiveness implies that emergency insertion of a copper IUC must prevent some pregnancies after fertilization.Emergency contraceptive pillsTo make an informed choice, women must know that ECPs—like the birth control pill, patch, ring, shot, and implant,76 and even like breastfeeding77—prevent pregnancy primarily by delaying or inhibiting ovulation and inhibiting fertilization, but may at times inhibit implantation of a fertilized egg in the endometrium. However, women should also be informed that the best available evidence indicates that ECPs prevent pregnancy by mechanisms that do not involve interference with post-fertilization events.ECPs do not cause abortion78 or harm an established pregnancy. Pregnancy begins with implantation according to medical authorities such as the US FDA, the National Institutes of Health79 and the American College of Obstetricians and Gynecologists (ACOG).80Ulipristal acetate (UPA). One study has demonstrated that UP can delay ovulation.81... Another study found that UPA altered the endometrium, but whether this change would inhibit implantation is unknown.82p. 122:Progestin-only emergency contraceptive pills. Early treatment with ECPs containing only the progestin levonorgestrel has been shown to impair the ovulatory process and luteal function.83–87p. 123:Combined emergency contraceptive pills. Several clinical studies have shown that combined ECPs containing ethinyl estradiol and levonorgestrel can inhibit or delay ovulation.107–110 p.3:How does EC work?In 2002, a judicial review ruled that pregnancy begins at implantation, not fertilisation.8 The possible mechanisms of action should be explained to the patient as some methods may not be acceptable, depending on individual beliefs about the onset of pregnancy and abortion.Copper-bearing intrauterine device (Cu-IUD). Copper is toxic to the ovum and sperm and thus the copper-bearing intrauterine device (Cu-IUD) is effective immediately after insertion and works primarily by inhibiting fertilisation.9–11 A systematic review on mechanisms of action of IUDs showed that both pre- and postfertilisation effects contribute to efficacy.11 If fertilisation has already occurred, it is accepted that there is an anti-implantation effect,12,13Levonorgestrel (LNG). The precise mode of action of levonorgestrel (LNG) is incompletely understood but it is thought to work primarily by inhibition of ovulation.16,17Ulipristal acetate (UPA). UPA's primary mechanism of action is thought to be inhibition or delay of ovulation.2Can LNG ECPs cause an abortion?LNG ECPs do not interrupt an established pregnancy or harm a developing embryo.15 The evidence available to date shows that LNG ECP use does not prevent a fertilized egg from attaching to the uterine lining. The primary mechanism of action is to stop or disrupt ovulation; LNG ECP use may also prevent the sperm and egg from meeting.16 p. 155: Emergency postcoital contraceptionLevonorgestrelMechanism and efficacy 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."Levonorgestrel-only emergency contraceptive pills:• Interfere with the process of ovulation;• May possibly prevent the sperm and the egg from meeting.Implications of the research:• Inhibition or delay of ovulation is LNG ECPs principal and possibly only mechanism of action.• Review of the evidence suggests that LNG-ECs cannot prevent implantation of a fertilized egg. Language on implantation should not be included in LNG ECP product labeling.• The fact that LNG-ECs have no demonstrated effect on implantation explains why they are not 100% effective in preventing pregnancy and are less effective the later they are taken. Women should be given a clear message that LNG-ECs are more effective the sooner they are taken.• LNG ECPs do not interrupt a pregnancy (by any definition of the beginning of pregnancy). However, LNG ECPs can prevent abortions by reducing unwanted pregnancies. 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 India, levonorgestrel for Emergency birth control was sold under the brand name i-pill. Introduced in 2007 by Cipla as an over-the-counter (OTC) medication, I‑Pill is marketed as a morning-after pill and remains one of the most widely used emergency contraceptive brands in India. The brand has become so prominent that its name is often used synonymously with birth control pills among women in India. The i-pill brand was sold to Piramal Healthcare Ltd in March 2010. Since then, Piramal Healthcare holds the manufacturing and marketing rights for i-pill in India.
In November 2013, the EMA 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.
An analysis of four WHO randomised clinical trials, published in January 2017, showed pregnancy rates of 1.25% (68/5428) in women with BMI under 25, 0.61% (7/1140) in women with BMI between 25 and 30, and 2.03% (6/295) in women with BMI over 30. Hence, while there are differences, emergency contraceptives remain effective regardless of BMI.
Hormone therapy Levonorgestrel is used in combination with an estrogen in menopausal hormone therapy. It is used under the brand name Klimonorm as a combined oral tablet with estradiol valerate and under the brand name Climara Pro as a combined transdermal patch with estradiol.
Available forms As a type of emergency contraception, levonorgestrel is used after unprotected intercourse to reduce the risk of pregnancy. However, it can serve different hormonal purposes in its different methods of delivery. It is available for use in a variety of forms:
By mouth Levonorgestrel can be taken by mouth as a form of emergency birth control. The typical dosage is either 1.5 mg taken once or 0.75 mg taken 12–24 hours apart. The effectiveness in both methods is similar. The most widely used form of oral emergency contraception is the progestin-only pill, which contains a 1.5 mg dosage of levonorgestrel. Levonorgestrel-only emergency contraceptive pills are reported to have an 89% effectiveness rate if taken within the recommended 72 hours after sex. The efficacy of the drug decreases by 50% for each 12-hour delay in taking the dose after the emergency contraceptive regimen has been started.
Skin patch
Estradiol with levonorgestrel in the form of a skin patch is used under the brand name Climara Pro for hormone replacement therapy in postmenstrual women, treating symptoms such as hot flashes or osteoporosis. The simultaneous delivery of a progestogen such as levonorgestrel is necessary for the protection of the endometrium.
Intrauterine device