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PREVEN Emergency Contraceptive Pills - Package Insert Information

Emergency Contraceptive Kit
consisting of Emergency Contraceptive Pills
(Levonorgestrel and Ethinyl Estradiol Tablets, USP)
and Pregnancy Test

Table of Contents

DESCRIPTION

The PREVENTM Emergency Contraceptive Kit is intended to prevent pregnancy after known or suspected contraceptive failure or unprotected intercourse. Emergency contraceptive pills (like all oral contraceptives) do not protect against infection with HIV (the virus that causes AIDS) and other sexually transmitted diseases.

The PREVENTM Emergency Contraceptive Kit consists of a patient information book, a urine pregnancy test and four (4) emergency contraceptive pills (ECPs).

The pills in the PREVENTM Emergency Contraceptive Kit are combination oral contraceptives (COCs) which are used to provide postcoital emergency contraception.

Each blue film-coated pill contains 0.25 mg levonorgestrel (18,19-Dinorpregn-4-en-20-yn-3-one, 13-Ethyl-17-hydroxy-, (17alpha)-(-), a totally synthetic progestogen, and 0.05 mg ethinyl estradiol (19-Nor-17alpha-pregna-1,3,5, (10)-trien-20-yne-3,17-diol). The inactive ingredients present are polacrilin potassium, lactose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, polysorbate 80 and FD&C Blue No.2 Aluminum Lake.

The Pregnancy Test uses monoclonal antibodies to detect the presence of hCG (Human Chorionic Gonadotropin) in the urine. It is sensitive to 20-25 mIU/mL.

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CLINICAL PHARMACOLOGY

ECPs are not effective if the woman is pregnant; they act primarily by inhibiting ovulation. They may also act by altering tubal transport of sperm and/or ova (thereby inhibiting fertilization), and/or possibly altering the endometrium (thereby inhibiting implantation).

Pharmacokinetics
Absorption. No specific investigation of the absolute bioavailability of the ECPs in humans have been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability about 100%) and it is not subject to first-pass metabolism. Ethinyl estradiol is rapidly absorbed from the gastrointestinal tract but due to marked metabolism in the gut mucosa and during passage through the liver, ethinyl estradiol absolute bioavailability after oral administration is about 40-50%.

After a single oral dose of two ECPs to 35 postmenopausal women under fasting conditions, the bioavailabilities of levonorgestrel and ethinyl estradiol were about 94% and 97%, respectively, relative to the same two active drugs given in an oral reference tablet. The obtained pharmacokinetic parameters for levonorgestrel and ethinyl estradiol are presented in Table 1. The effect of food on the bioavailability of the ECPs following oral administration has not been evaluated.

Table 1. Mean (SD) Pharmacokinetic Parameters after oral dose of 2 ECPs

Levonorgestrel (n=35)
Cmax
ng/mL
Tmax
h
AUC
ng/mL*h
T1/2
h
10.9 (4.0) 1.7 (1.0) 167 (92) 40.8 (19.2)

Ethinyl Estradiol (n=35)
Cmax
pg/mL
Tmax
h
AUC
pg/mL*h
T1/2
h
248.2 (67) 1.7 (0.4) 2747 (701) 21.2 (9.3)

Distribution. 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.

Metabolism
Levonorgestrel: The most important metabolic pathways occur in the reduction of the 4-3-oxo group and hydroxylation at positions 2 alpha, 10ß, 16ß, followed by conjugation. Most of the metabolites that circulate in the blood are sulfates of 3alpha, 5ß-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. Some of the parent levonorgestrel also circulates as 17ß-sulfate. Metabolic clearance rates may differ among individuals by several fold, and this may account in part for the high variability observed in levonorgestrel concentrations among users.

Ethinyl Estradiol: The cytochrome P450 enzyme (CYP3A4) is 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 faeces as glucoronides and sulfates and undergoes enterohepatic circulation.

Excretion. The elimination half-life for levonorgestrel after a single dose of two ECPs is 40.8 ± 19 hours. Levonorgestrel and its metabolites are primarily excreted in the urine. The elimination half-life of ethinyl estradiol is 21.2 ± 9.3 hours.

Special Populations. This product is not intended for use in geriatric (age 65 or older) or pediatric (premenarchal) populations and pharmacokinetic data are unavailable for these populations. Steroid hormones may be poorly metabolized in patients with impaired liver function (see Precautions-Liver Function).

Race, Hepatic Insufficiency, and Renal insufficiency: No formal studies have evaluated the effect of race, hepatic disease and renal disease on the disposition of the ECPs.

Drug-Drug Interactions. No specific drug-drug interaction studies for the ECPs were conducted but there are many publications that indicate that interactions between ethinyl estradiol and other drugs may occur. Other drugs may decrease the effectiveness of ethinyl estradiol or other drugs may enhance ethinyl estradiol levels resulting in possible increased side-effects. Ethinyl estradiol may interfere with the metabolism of other compounds. In general, the effect of other drugs on ethinyl estradiol is due to interference with the absorption, metabolism or excretion of ethinyl estradiol, whereas the effect of ethinyl estradiol on other drugs is due to competition for metabolic pathways.

  • Absorption interactions: Infective diarrhea may induce failure of ethinyl estradiol by increasing gastrointestinal motility and reducing hormone absorption. Therefore, any drug which increases gastrointestinal transit and causes diarrhea is potentially likely to reduce concentrations of ethinyl estradiol.
  • Interactions with metabolism:
    • Gastrointestinal Wall: The gastrointestinal wall has been shown to be a site for interaction for the sulfation of ethinyl estradiol. Inhibition of the sulfation in the gastrointestinal tract may increase the bioavailability of ethinyl estradiol and result in possible increased side-effects. (For example, ascorbic acid acts as a competitive inhibitor for sulfation in the gastrointestinal wall increasing ethinyl estradiol bioavailability about 50%.)
    • Hepatic Metabolism: The most clinically significant group of interactions occurs with other drugs that may induce ethinyl estradiol microsomal enzymes which may decrease ethinyl estradiol plasma levels below therapeutic level (for example, anticonvulsant agents; phenytoin, primidone, barbiturates, carbamazepine, ethosuximide, and methosuximide; antituberculous drugs such as rifampin; antifungal drugs such as griseofulvin).
  • Interference with enterohepatic circulation: Ethinyl estradiol conjugates are excreted in the bile and may be broken down by gut bacteria in the colon to liberate the active hormone which can then be reabsorbed. However, there are clinical reports that support the view that enterohepatic circulation of ethinyl estradiol decreases in women taking antibiotics such as ampicillin, tetracycline, etc.
    • Interference in the metabolism of other drugs: Ethinyl estradiol can inhibit microsomal enzymes and therefore possibly interfere in the metabolism of other drugs. In this way it may slow the metabolism of other drugs, increasing their plasma and tissue concentrations and increasing the risk of side-effects (i.e., analgesic anti-inflammatory drugs such as antipyrin, antidepressant agents, cyclosporin, theophylline, ethanol, etc.). In addition, estrogens appear to have the capacity to induce hepatic drug conjugation, particularly glucuronidation. This will have the opposite pharmacokinetic effect to the inhibitory action on hydroxylation.

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INDICATIONS AND USAGE

Indications. The pills in PREVENTM Emergency Contraceptive Kit are indicated for the prevention of pregnancy in women after known or suspected contraceptive failure or unprotected intercourse. To obtain optimal efficacy, use of these pills should begin as soon as possible but within 72 hours of intercourse.

Efficacy. If one hundred women used ECPs correctly in one month, about two women would become pregnant after a single act of intercourse. If no contraception is used about eight women would become pregnant after a single act of intercourse. Therefore, the use of ECPs results in a 75% reduction in the number of pregnancies to be expected if no ECPs were used after unprotected intercourse. Notably some clinical trials have shown that efficacy was greatest when ECPs were taken within 24 hours of unprotected intercourse, decreasing somewhat during each subsequent 24-hour period.

ECPs are not as effective as some other forms of contraception. For effectiveness rates of other contraceptive methods, refer to Table 2: Percentage of women experiencing an unintended pregnancy during the first year of perfect use of contraception and the percentage continuing use at the end of the first-year of perfect use of contraception and the percentage continuing use at the end of the first year -United States.

Table 2: Percentage of women experiencing an unintended pregnancy during the first year of typical use and the first year of contraception and the percentage continuing use at the end of the first year. United States.

  % of Women Experiencing an Unintended Pregnancy within the First Year of Use % of Women Continuing Use at One Year
Method
(1)
Typical Use1
(2)
Perfect Use2
(3)
 
(4)
Chance4 85 85  
Spermicides5 26 6    40  

Periodic abstinence

   Calendar

   Ovulation Method

   Symptom-thermal6

   Post-ovulation

 25

 

9

3

2

1

63 

 

 

 

Withdrawal  19  4  

Cap7

   Parous Women

   Nulliparous Women

 

40

20

 

26

9

 

42

56

Sponge

   Parous women

   Nulliparous women

 

40

20

 

20

9

 

42

56

 Diaphragm7  20  56

Condom8

   Female (Reality)

   Male

 

21

14

 

5

3

 

56

56

Oral Contraceptives

   Progestin Only

   Combined

 

0.5

0.1

71  

 IUD

   Progestin T

   Copper T 380A

   LNG

 

2.0

0.8

0.1

 

1.5

0.6

0.1

 

81

78

81

Depo-Provera 0.3  0.3    
Norplant and Norplant-2  0.05  0.05  88
Female Sterilization 0.5  0.5  100 
Male Sterilization 0.15  0.10   100 

Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.
Lactational Amenorrhea Method: LAM is a highly effective temporary method of contraception.9

  1. Among typical couples who initiate use of a method (not necessarily for the first time) 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 percent 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 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. However, to maintain an 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 six months of age.

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

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CONTRAINDICATIONS

The pills provided in the PREVENTM Emergency Contraceptive Kit are combination oral contraceptive (COC) pills. The following are the known CONTRAINDICATIONS of daily cyclical combination oral contraceptive pill use (1 pill each day for 21 days of a 28-day cycle). It is not known whether these contraindications also apply to the ECP regimen of four oral contraceptive pills taken within a 12-hour period.

  • Known or suspected pregnancy
  • Pulmonary embolism (current or history)
  • Ischemic heart disease (current or history)
  • History of cerebrovascular accidents
  • Valvular heart disease with complications
  • Severe hypertension
  • Diabetes with vascular involvement
  • Headaches with focal neurological symptoms
  • Major surgery with prolonged immobilization
  • Known or suspected carcinoma of the breast or personal history of breast cancer
  • Liver tumors (benign and malignant) active liver disease
  • Heavy smoking (>15 cigarettes per day) and over the age of 35
  • In addition, use is contraindicated in women who are known to be hypersensitive to any component of this product.

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WARNINGS

The pills provided in the PREVENTM Emergency Contraceptive Kit are combination oral contraceptive (COC) pills. The following are the WARNINGS given for daily cyclical combination oral contraceptive pill use (1 pill each day for 21 days of a 28-day cycle). It is not known whether these warnings also apply to the ECP regimen of four oral contraceptive pills taken within a 12-hour period.


Women who use COCs should be strongly advised not to smoke. Cigarette smoking increases the risk of serious cardiovascular side effects. This risk increases with age (over 35) and smoking of more than 15 cigarettes per day.

1. Cardiovascular disease (CVD). COC use is associated with a small increase in the incidence of cardiovascular disease (CVD), primarily because of an increased risk of thrombosis rather than through an atherogenic mechanism. The degree of risk appears to be related primarily to the estrogen dosage. This increased risk is limited to the period during COC use and disappears upon cessation of use. Because the incidence of CVD is low during the reproductive years, the absolute risk attributable to COC use is quite small.
a. Deep Vein Thrombosis, Pulmonary Embolism. Use of COCs is associated with a low absolute risk of venous thromboembolism which is nonetheless 3- to 6-fold higher than that among non-users. Smoking does not appear to be a risk factor.
The presence of factor V Leiden mutation and other hereditary coagulation disorders increases the risk of thromboembolic disease.
COC use is contraindicated for women who have deep vein thrombosis or pulmonary embolism and for those who have a history of these conditions.

Women who are immobilized for prolonged periods because of major surgery (or illness or injury) should not use COCs. For women undergoing major surgery without prolonged immobilization, the advantages of COC use generally outweigh the risk. COC use should preferably not begin until 2-3 weeks postpartum, because of the risk of thrombosis.

b. Cerebrovascular disease. In women who do not smoke and do not have hypertension, the risk of ischemic stroke in users of COCs is increased about 1.5 fold compared with non-users. The likelihood of hemorrhagic stroke is not increased among users of low-dose combined COCs who are under 35 years old and do not smoke or have hypertension. Women who have a history of stroke should not use COCs.

c. Ischemic heart disease. The likelihood of myocardial infarction is not increased among young women who use COCs and do not smoke or have hypertension or diabetes. Smokers older than 35 should not take COCs. Women who currently have ischemic heart disease, or who have a history of this disease, should not use COCs.

d. Valvular heart disease. COC use is contraindicated for women whose valvular heart disease is complicated by such factors as pulmonary hypertension, atrial fibrillation, or history of sub-acute bacterial endocarditis. COC use may be acceptable for women with uncomplicated valvular heart disease.

2. Elevated blood pressure. For women with an elevation in blood pressure (160+/100+mmHg), COC use would present an unacceptable health risk, and COCs should not be used. Similarly, hypertensive women with vascular disease should not use COCs.

3. Ocular Lesions. There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions.

4. Carbohydrate metabolism. For women with diabetes (both insulin-dependent and non-insulin dependent), who do not have vascular involvement, the advantages of COC use generally outweigh the risks, particularly the risks associated with pregnancy. The major concerns are vascular disease and added risk of thrombosis, although COC use by diabetic women appears to have only minimal effects on lipid metabolism and hemostasis. For diabetic women with nephropathy, retinopathy, neuropathy, or other vascular involvement, the risk-benefit ratio depends on the severity of the condition.

5. Headaches. For women with severe, recurrent headaches, including migraine headaches, the appropriateness of using COCs depends on the presence or absence of focal neurologic symptoms. These symptoms may reflect an increased risk of stroke and COC use is contraindicated in patients in whom they are present. The onset or exacerbation of migraines or the development of severe headache with focal neurological symptoms, which are recurrent or persistent, requires discontinuation of COC use and evaluation of the cause.

6. Unexplained vaginal bleeding. Women who have unexplained vaginal bleeding, suggestive of an underlying pathological condition or pregnancy, should be evaluated prior to initiation of COC use in order to avoid confusion of the pathological bleeding with COC side effects.

7. Liver Disease. Because steroid hormones are metabolized by the liver, women taking COCs may experience adverse hepatobiliary effects. Although case-control studies have indicated that the risk of both benign and malignant liver tumors may be slightly increased by COC use, the incidence potentially attributable to COCs in the United States is minimal because the disease is very rare. Women who currently have active liver disease should not use COCs.

8. Ectopic Pregnancy. Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.

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PRECAUTIONS

1. Sexually transmitted diseases. Women should be informed that this product does not protect against infection with HIV (the virus that causes AIDS) and other sexually transmitted diseases (STDs). If a woman is at high risk for STDs she should be encouraged to reduce risky behavior and to use condoms or other barrier methods (in addition to COCs).

2. Pregnancy. Extensive research has found no significant effects on fetal development associated with long-term use of contraceptive doses of oral steroids before pregnancy or taken inadvertently during early pregnancy.

3. Nursing mothers. Oral contraceptive steroids have been reported in the milk of breast feeding mothers with no apparent clinical significance; long-term follow-up of children whose mothers used COCs while breastfeeding has shown no deleterious effects.

4. Pediatric use. The safety and efficacy of COCs have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under 16 and users 16 and older. Use of this product before menarche is not indicated.

5. Repeated use of Emergency Contraceptive Pills. The effect of repeated use of ECPs (more than once in a menstrual cycle or in multiple cycles) is unknown.

6. Information for the patient. Please see separate patient labeling information.

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ADVERSE REACTIONS

The pills provided in the PREVENTM Emergency Contraceptive Kit are combination oral contraceptive (COC) pills. Based on clinical experience over several years of use of ECPs the most common side effects reported were as follows:

  • Nausea
  • Vomiting
  • Menstrual irregularities
  • Breast tenderness
  • Headache
  • Abdominal pain /cramps
  • Dizziness

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DOSAGE AND ADMINISTRATION

The PREVENTM Emergency Contraceptive Kit contains a pregnancy test. This test can be used to verify an existing pregnancy resulting from intercourse that occurred earlier in the current menstrual cycle or the previous cycle. If a positive pregnancy result is obtained, the patient should not take the pills in the PREVENTM Kit.

The initial two pills must be taken as soon as possible but within 72 hours of unprotected intercourse. This is followed by the second dose of two pills 12 hours later. The patient should be instructed that if she vomits within one hour of taking either dose of the medication, she should contact her healthcare professional to discuss whether to repeat that dose or to take an antinausea medication. ECPs are not indicated for ongoing pregnancy protection and should not be used as a woman's routine form of contraception.

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HOW SUPPLIED

The PREVENTM Emergency Contraceptive Kit (NDC No.63955-010-01) is available in a carton which includes a patient information book, a pregnancy test in a sealed foil pack, a blister pack containing 4 emergency contraceptive pills (ECPs) and detailed patient labeling.

Each pill contains 0.25 mg levonorgestrel and 0.05 mg ethinyl estradiol. The pills are marked with a G on one side and the numerals 891 on the other.

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).

(See USP Controlled Room Temperature)

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