MICROGYNON

Levonorgestrel (LNG) is a synthetic progestogen similar to Progesterone used in contraception and hormone therapy. 7, 18 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. 8, 19, 21 Globally, levonorgestrel is the most commonly used emergency contraceptive.

It was initially granted

FDA approval in 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. 3, 9, 19.

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. 3, 19 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. 21, 22, 23 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. 21, 30 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.

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. 3, 7 The intrauterine and implantable devices releasing levonorgestrel are more than 99% in preventing pregnancy. 14, 21, 22 Levonorgestrel utilized as a component of hormonal therapy helps to prevent endometrial carcinoma associated with unopposed estrogen administration.

Progesterone receptor

Modulator 3-oxo-5-alpha-steroid 4-dehydrogenase 1 Inhibitor Estrogen receptor Other/unknown.

Oral 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.

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 197.28-208.1 h × ng/mL in an obese group of patients.

Obesity may contribute to decreased efficacy of levonorgestrel in contraception.

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.

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.

CYP3A4 and CYP3A5 hepatic enzymes are reported to be involved in the metabolism of levonorgestrel. 17, 19 Hover over products below to view reaction partners Levonorgestrel Glucuronide conjugates, levonorgestrel + Sulfate conjugates, levonorgestrel 16βhydroxylevonorgestrel + 3α, 5β-tetrahydrolevonorgestrel.

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 Oral ingested dose is found excreted in feces, primarily in the form of glucuronide conjugates of levonorgestrel.

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.

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.

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The oral

LD50 in rats is greater than 5000 mg/kg.

An overdose of this drug, like other contraceptives, may cause nausea and withdrawal bleeding.

Provide symptomatic treatment in the case of a levonorgestrel overdose and contact the local poison control center.

There is no specific antidote for a levonorgestrel overdose. 19, 25, 26.

Iclevia is contraindicated in females who are known to have or develop the following conditions: A high risk of arterial or venous thrombotic diseases.

Examples include females who are known to: Smoke, if over age 35.

Have current or history of deep vein thrombosis or pulmonary embolism.

Have cerebrovascular disease.

Have coronary artery disease.

Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) .

Have inherited or acquired hypercoagulopathies.

Have uncontrolled hypertension or hypertension with vascular disease.

Have diabetes mellitus and are over age of 35, diabetes mellitus with hypertension or vascular disease or other end-organ damage, or diabetes mellitus of >20 years duration.

Have headaches with focal neurological symptoms, migraine headaches with aura, or over age with any migraine headaches.

Current diagnosis of, or history of breast cancer, which may be hormone sensitive.

Liver tumors, acute viral hepatitis, or severe (decompensated) cirrhosis.

Undiagnosed abnormal uterine bleeding.

C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations.

A high risk of arterial or venous thrombotic diseases Liver tumors or liver disease, acute viral hepatitis or decompensated cirrhosis Undiagnosed abnormal uterine bleeding Breast cancer Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir.

Take one tablet daily by mouth at the same time every day for 91 days.

Take tablets in the order directed on the Extended-Cycle Wallet. 2.1 How to Start and Take Iclevia Iclevia is dispensed in an Extended-Cycle Wallet.

Iclevia should be started on a

For the first cycle of a Sunday Start regimen, an additional method of contraception should be used until after the first 7 consecutive days of administration.

Table 1: Instructions for Administration of Iclevia Starting Iclevia in females with no current use of hormonal contraception (Sunday Start) Important: Consider the possibility of ovulation and conception prior to initiation of this product.

Iclevia active tablets are white (Day to Day 84).

Iclevia inactive tablets are green (Day to Day 91).

For each 91-day course, take in the following order: Take the first white tablet (0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol) on the first Sunday after the onset of menstruation.

If menstruation begins on a

Sunday, take the tablet on that day. Due to the potential risk of becoming pregnant, use additional non-hormonal contraception (such as condoms or spermicide) for the first 7 days of treatment.

Take subsequent white tablets once daily at the same time each day for a total of 84 days.

Take one green tablet (inert) daily for the following 7 days and at the same time of day that active tablets were taken.

A scheduled period should occur during the 7 days that the green tablets are taken.

Begin the next and all subsequent 91-day courses of Iclevia without interruption on the same day of the week (Sunday) on which the patient began her first dose.

Follow the same schedule as the initial 91-day course: a white tablet once a day for 84 days, and a green tablet once a day for 7 days.

If the patient does not immediately start her next pill pack, instruct her to protect herself from pregnancy by using a non-hormonal back-up method of contraception until she has taken a white tablet daily for 7 consecutive days.

Switching from another contraceptive method to Iclevia Start Iclevia: Another oral contraceptive On the day when the new pack of the previous COC would have been started Transdermal patch On the day when the next application would have been scheduled.

Vaginal ring

On the day when the next insertion would have been scheduled.

On the day when the next injection would have been scheduled.

Intrauterine contraceptive (IUD) On the day of removal.

If the

IUD is not removed on first day of the patient’s menstrual cycle, additional non.

• hormonal contraception (such as condoms or spermicide) is needed for the first seven days of the first 91-day course.

On the day of removal.

Starting Iclevia after Abortion or Miscarriage First-trimester After a first-trimester abortion or miscarriage, Iclevia may be started immediately.

An additional method of contraception is not needed if Iclevia is started immediately.

If Iclevia is not started within 5 days after termination of the pregnancy, the patient should use additional non-hormonal contraception (such as condoms or spermicide) for the first seven days of her first 91-day course of Iclevia.

Second-trimester Do not start

Iclevia until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease.

Start Iclevia following the instructions in Table for Sunday start.

Use additional non-hormonal contraception (such as condoms or spermicide) for the first seven days of the patient’s first 91-day course of Iclevia.

Starting Iclevia after Childbirth Do not start Iclevia until 4 weeks after delivery, due to the increased risk of thromboembolic disease.

Start contraceptive therapy with Iclevia following the instructions in Table for women not currently using hormonal contraception.

Iclevia is not recommended for use in lactating women.

If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of Iclevia. 2.2 Dosing Iclevia Instruct patients to take one tablet by mouth at the same time every day. The dosing of Iclevia is one white pill containing levonorgestrel and ethinyl estradiol daily for 84 consecutive days, followed by one green pill (inactive pills without hormone) for 7 days.

To achieve maximum contraceptive effectiveness, Iclevia must be taken exactly as directed, in the order directed on the Wallet, and at intervals not exceeding 24 hours.

Start taking the first white pill from a new Wallet the very next day after taking the last green inactive pill in the Wallet.

The failure rate may increase when pills are missed or taken incorrectly. 2.3 Missed Doses Table 2: Instructions for Missed Iclevia Tablets If one active tablet (white) is missed in Days 1 through 84 Take the tablet as soon as possible.

Take the next tablet at the regular time and continue taking one tablet a day until the 91-day course is finished.

If two consecutive active tablets (white) are missed in Days 1 through 84 Take 2 tablets on the day remembered and 2 tablets the next day. Then continue taking one tablet a day until the 91-day course is finished.

Additional non-hormonal contraception (such as condoms or spermicide) should be used as back-up if the patient has sex within 7 days after missing tablets.

If three or more consecutive active tablets (white) are missed in Days 1 through 84 Do not take the missed tablets.

Continue taking one tablet a day until the 91-day course is finished.

Additional non-hormonal contraception (such as condoms or spermicide) must be used as back-up if the patient has sex within 7 days after missing tablets.

If any of the seven green (inactive) tablets are missed Throw away the missed tablets.

Continue taking the remaining tablets until the pack is finished.

A backup birth control method is not needed. 2.4 Advice in Case of Gastrointestinal Disturbances In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken.

If vomiting or diarrhea occurs within to 4 hours after taking a white tablet, handle this as a missed tablet.

Iclevia (levonorgestrel and ethinyl estradiol tablets USP) are available in Extended-Cycle Wallets, each containing a 13-week supply of tablets in the following order: 84 white tablets, each containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol; round, biconvex, beveled-edge tablets debossed with “S” on one side and “27” on other side. 7 green inert tablets; round, mottled, biconvex, beveled-edge uncoated tablets, debossed with “S” on one side and “61” on other side of the tablet.

Pouch of 1 Extended-Cycle Wallet NDC 65862.

• 865-94 Carton of 3 Pouches NDC 65862.

• 865-83 Storage and Handling Store at 20º to 25°C (68° to 77º F) .

Protect from light.

There is no use for contraception in pregnancy; therefore, Iclevia should be discontinued during pregnancy.

Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to COCs before conception or during early pregnancy.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4 percent and to 20 percent, respectively.

Safety and efficacy of levonorgestrel and ethinyl estradiol tablets have been established in women of reproductive age.

Efficacy is expected to be the same for postpubertal adolescents under the age of as for users 18 years and older.

Use of levonorgestrel and ethinyl estradiol tablets before menarche is not indicated.

Levonorgestrel and ethinyl estradiol tablets has not been studied in postmenopausal women and is not indicated in this population.