Orsythia

Ethinyl estradiol and levonorgestrel is a combination birth control pill containing female hormones that prevent ovulation (the release of an egg from an ovary). This medicine also causes changes in your cervical mucus and uterine lining, making it harder for sperm to reach the uterus and harder for a fertilized egg to attach to the uterus.

Ethinyl estradiol and levonorgestrel is used as contraception to prevent pregnancy. There are many available brands of ethinyl estradiol and levonorgestrel. Not all brands are listed on this leaflet.

Ethinyl estradiol and levonorgestrel may also be used for purposes not listed in this medication guide.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Follow how to use as you have been told by the doctor or read the package insert.
• Take Orsythia at the same time of day.
• Take with or without food. Take with food if it causes an upset stomach.
• Do not skip doses, even if you do not have sex very often.
• If you throw up or have diarrhea, this medicine may not work as well to prevent pregnancy. Use an extra form of birth control, like condoms, until you check with your doctor.
• If your monthly cycle is 28 days and you miss 2 periods in a row, take a pregnancy test before starting a new dosing cycle.
• If you have a cycle longer than 91 days and you miss one period, take a pregnancy test before starting a new dosing cycle.

What do I do if I miss a dose?

• If a dose is missed, check the package insert or call the doctor to find out what to do. If using Orsythia to prevent pregnancy, another form of birth control may need to be used for some time to prevent pregnancy.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

21 pink active tablets each containing 0.1 mg of levonorgestrel, d(-)-13β-ethyl-17α-ethinyl-17β-hydroxygon-4-en-3-one, a totally synthetic progestogen, and 0.02 mg of ethinyl estradiol, 17α-ethinyl-1,3,5(10)-estratriene-3, 17β-diol. The inactive ingredients present are FD&C red #40 aluminum lake, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, pregelatinized starch and vitamin E.

7 light-green inert tablets, each containing FD&C blue #2, hypromellose, iron oxide yellow, lactose monohydrate, magnesium stearate, polyethylene glycol and pregelatinized starch.

Mode of Action

Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).

Pharmacokinetics

No specific investigation of the absolute bioavailability of levonorgestrel and ethinyl estradiol in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability about 100%) and is not subject to first-pass metabolism. Ethinyl estradiol is rapidly and almost completely absorbed from the gastrointestinal tract but, due to first-pass metabolism in gut mucosa and liver, the bioavailability of ethinyl estradiol is between 38% and 48%.

After a single dose of levonorgestrel and ethinyl estradiol to 22 women under fasting conditions, maximum serum concentrations of levonorgestrel are 2.8 ± 0.9 ng/mL (mean ± SD) at 1.6 ± 0.9 hours. At steady state, attained from day 19 onwards, maximum levonorgestrel concentrations of 6.0 ± 2.7 ng/mL are reached at 1.5 ± 0.5 hours after the daily dose. The minimum serum levels of levonorgestrel at steady state are 1.9 ± 1.0 ng/mL. Observed levonorgestrel concentrations increased from day 1 (single dose) to days 6 and 21 (multiple doses) by 34% and 96%, respectively (FIGURE I). Unbound levonorgestrel concentrations increased from day 1 to days 6 and 21 by 25% and 83%, respectively. The kinetics of total levonorgestrel are non-linear due to an increase in binding of levonorgestrel to sex hormone binding globulin (SHBG), which is attributed to increased SHBG levels that are induced by the daily administration of ethinyl estradiol.

Following a single dose, maximum serum concentrations of ethinyl estradiol of 62 ± 21 pg/mL are reached at 1.5 ± 0.5 hours. At steady state, attained from at least day 6 onwards, maximum concentrations of ethinyl estradiol were 77 ± 30 pg/mL and were reached at 1.3 ± 0.7 hours after the daily dose. The minimum serum levels of ethinyl estradiol at steady state are 10.5 ± 5.1 pg/mL. Ethinyl estradiol concentrations did not increase from days 1 to 6, but did increase by 19% from days 1 to 21 (FIGURE I).

TABLE I provides a summary of levonorgestrel and ethinyl estradiol pharmacokinetic parameters.

Levonorgestrel in serum is primarily bound to SHBG. Ethinyl estradiol is about 97% bound to plasma albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis.

Levonorgestrel

The most important metabolic pathway occurs in the reduction of the Δ4-3-oxo group and hydroxylation at positions 2α, 1β, and 16β, followed by conjugation. Most of the metabolites that circulate in the blood are sulfates of 3α, 5β-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. Some of the parent levonorgestrel also circulates as 17β-sulfate. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users.

Ethinyl estradiol

Cytochrome P450 enzymes (CYP3A4) in the liver are responsible for the 2-hydroxylation that is the major oxidative reaction. The 2-hydroxy metabolite is further transformed by methylation and glucuronidation prior to urinary and fecal excretion. Levels of Cytochrome P450 (CYP3A) vary widely among individuals and can explain the variation in rates of ethinyl estradiol 2-hydroxylation. Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates, and undergoes enterohepatic circulation.

The elimination half-life for levonorgestrel is approximately 36 ± 13 hours at steady state. Levonorgestrel and its metabolites are primarily excreted in the urine (40% to 68%) and about 16% to 48% are excreted in feces. The elimination half-life of ethinyl estradiol is 18 ± 4.7 hours at steady state.

Special Populations

Based on the pharmacokinetic study with levonorgestrel and ethinyl estradiol, there are no apparent differences in pharmacokinetic parameters among women of different races.

No formal studies have evaluated the effect of hepatic disease on the disposition of levonorgestrel and ethinyl estradiol. However, steroid hormones may be poorly metabolized in patients with impaired liver function.

No formal studies have evaluated the effect of renal disease on the disposition of levonorgestrel and ethinyl estradiol.

Drug-Drug Interactions

See PRECAUTIONS, Drug Interactions.

Orsythia® (levonorgestrel and ethinyl estradiol tablets USP) is indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.

Oral contraceptives are highly effective. TABLE II lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and levonorgestrel implants, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.

Emergency Contraceptive Pills: The FDA has concluded that certain combined oral contraceptives containing ethinyl estradiol and norgestrel or levonorgestrel are safe and effective for use as postcoital emergency contraception. Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.9

Lactation Amenorrhea Method: LAM is a highly effective, temporary method of contraception.10

Source: Trussell J. Contraceptive efficacy. In: Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowel D, Guest F. Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers; 1998.

1 Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.

2 Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.

3 Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year.

4 The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether.

5 Foams, creams, gels, vaginal suppositories, and vaginal film.

6 Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases.

7 With spermicidal cream or jelly.

8 Without spermicides.

9 The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. The FDA has declared the following dosage regimens of oral contraceptives to be safe and effective for emergency contraception: for tablets containing 50 mcg of ethinyl estradiol and 500 mcg of norgestrel 1 dose is 2 tablets; for tablets containing 20 mcg of ethinyl estradiol and 100 mcg of levonorgestrel 1 dose is 5 tablets; for tablets containing 30 mcg of ethinyl estradiol and 150 mcg of levonorgestrel 1 dose is 4 tablets.

10 However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches 6 months of age.

In a clinical trial with levonorgestrel and ethinyl estradiol tablets, 1,477 subjects had 7,720 cycles of use and a total of 5 pregnancies were reported. This represents an overall pregnancy rate of 0.84 per 100 woman-years. This rate includes patients who did not take the drug correctly. One or more pills were missed during 1,479 (18.8%) of the 7,870 cycles; thus all tablets were taken during 6,391 (81.2%) of the 7,870 cycles. Of the total 7,870 cycles, a total of 150 cycles were excluded from the calculation of the Pearl index due to the use of back-up contraception and/or missing 3 or more consecutive pills.

Combination oral contraceptives should not be used in women with any of the following conditions:

Thrombophlebitis or thromboembolic disorders

A history of deep-vein thrombophlebitis or thromboembolic disorders

Cerebrovascular or coronary artery disease (current or past history)

Valvular heart disease with thrombogenic complications

Thrombogenic rhythm disorders

Hereditary or acquired thrombophilias

Major surgery with prolonged immobilization

Diabetes with vascular involvement

Headaches with focal neurological symptoms

Uncontrolled hypertension

Known or suspected carcinoma of the breast or personal history of breast cancer

Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia

Undiagnosed abnormal genital bleeding

Cholestatic jaundice of pregnancy or jaundice with prior pill use

Hepatic adenomas or carcinomas, or active liver disease

Known or suspected pregnancy

Hypersensitivity to any of the components of levonorgestrel and ethinyl estradiol

Are receiving Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations (see Warnings, RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT).

The following noncontraceptive health benefits related to the use of oral contraceptives are supported by epidemiological studies which largely utilized oral-contraceptive formulations containing doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg of mestranol.

Effects on menses:
Increased menstrual cycle regularity
Decreased blood loss and decreased incidence of iron-deficiency anemia
Decreased incidence of dysmenorrhea

Effects related to inhibition of ovulation:
Decreased incidence of functional ovarian cysts
Decreased incidence of ectopic pregnancies

Effects from long-term use:
Decreased incidence of fibroadenomas and fibrocystic disease of the breast
Decreased incidence of acute pelvic inflammatory disease
Decreased incidence of endometrial cancer
Decreased incidence of ovarian cancer

Orsythia® (levonorgestrel (0.1 mg) and ethinyl estradiol (0.02 mg) tablets USP) is packaged in cartons of 3 and 6 blister pack tablet dispensers. Each blister pack tablet dispenser contains 28 tablets as follows: 

21 active tablets, pink, round, film-coated tablet debossed with "93" on one side and "684" on the other side.

7 inert tablets, light-green, round, film-coated tablet debossed with "93" on one side and "743" on the other side.

Blister pack tablet dispenser NDC 0603-7634-01
Boxes of 3 blister pack tablet dispensers NDC 0603-7634-49
Boxes of 6 blister pack tablet dispensers NDC 0603-7634-17

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

References available upon request.

Manufactured In Canada By:
Patheon Inc.
Ontario, Canada L5N 7K9

Manufactured For:
QUALITEST PHARMACEUTICALS USA 
Huntsville, AL 35811

Rev. 5/2017

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Feeling more or less hungry.
• Dizziness.
• Weight gain.
• Headache.
• Upset stomach or throwing up.
• Cramps.
• Bloating.
• Enlarged breasts.
• Breast soreness.
• Hair loss.
• Pimples (acne).
• Period (menstrual) changes. These include spotting or bleeding between cycles.
• Lowered interest in sex.
• This drug may cause dark patches of skin on your face. Avoid sun, sunlamps, and tanning beds. Use sunscreen and wear clothing and eyewear that protects you from the sun.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.