Pharmacology Consult

Emergency contraception decoded: Discussing cost, efficacy and access

In 2011, approximately 45% of the more than 6 million annual pregnancies in the United States were unintended, according to a study by Finer and colleagues in The New England Journal of Medicine. Among teens aged 15 to 19 years, approximately 6% become pregnant each year, with more than 80% of these pregnancies unplanned.

Although numerous forms of highly effective planned contraception are available, each of these methods entails potential limitations, including adherence, cost, and availability and access, among others. In the event of failed contraception due to inappropriate contraceptive product use, lack of use of a contraceptive product or sexual assault, emergency contraception (EC) products can provide an effective alternative to prevent unintended pregnancy.

Edward A. Bell

Of the three orally administered forms of EC currently available in the U.S., levonorgestrel — the active enantiomer of the progestogen norgestrel — is likely the most well-known to health care providers. Contained in Plan B One-Step (Teva Pharmaceuticals) as a single 1.5-mg tablet, levonorgestrel is available over the counter (OTC) without any age restrictions. A second form of EC is Ella (ulipristal acetate, Afaxys), in a single 30-mg tablet, which is available only by prescription.

Lastly, the Yuzpe method — named for Canadian gynecologist, Albert Yuzpe, MD, MSc — is a two-dose EC regimen employing any number of different combination estrogen/progestogen oral contraceptive tablet products that yield a dose of 100 µg of ethinyl estradiol plus 500 µg levonorgestrel, with a second dose given 12 hours later. For example, the oral contraceptive product Amethyst (Actavis Pharma) contains 20 µg of ethinyl estradiol and 90 µg of levonorgestrel per tablet; therefore, six tablets of Amethyst provides a dose of 120 µg of ethinyl estradiol and 540 µg of levonorgestrel (with a second dose given 12 hours later), using the Yuzpe method.

However, health care providers should note that some oral contraceptive products contain norgestrel as the progestogen product, and because norgestrel is a racemic mixture, a dose of 1,000 µg must be used to provide 500 µg of levonorgestrel. For example, Lo/Ovral (Wyeth Pharmaceuticals) contains 50 µg of ethinyl estradiol and 500 µg of norgestrel (equivalent to 250 µg of levonorgestrel) per tablet. Two tablets of Lo/Ovral, with a second dose repeated in 12 hours, provides a necessary Yuzpe method EC dose.

Shifting regulations

There have been significant changes in the regulatory and product availability for EC pharmacotherapies over the past 5 to 10 years. Following several years of turbulent political debate between medical organizations and social conservative groups, in 2006, the FDA approved levonorgestrel for OTC use for patients aged 18 years or older. The FDA would eventually eliminate this age limit and the need for a prescription, in 2013, to allow the sale of Plan B One-Step; 3 years later, prescription and age restrictions were likewise removed from generic levonorgestrel products as well.

Although all three orally administered EC products are effective if used within 120 hours of unprotected sex, some differences remain in efficacy and risk factors. Comparative controlled studies have demonstrated that the most effective EC product is ulipristal, with pregnancy failure rates of 0.9% to 2.1%, followed by levonorgestrel with pregnancy failure rates of 0.6% to 3.1%. The Yuzpe method is least effective. Although it can also be relied upon to provide effective EC when dosed and administered appropriately, it should be used only if levonorgestrel or ulipristal are not available.

Prior studies have indicated that efficacy does not decline within the 120-hour period for ulipristal, but evidence suggests efficacy may decline for levonorgestrel. No evidence exists to document efficacy for orally administered EC products administered after 120 hours following unprotected sex; EC products function to delay or inhibit ovulation as the primary mechanism to prevent pregnancy. Although limited and equivocal, some studies have indicated that efficacy may be reduced in women with a BMI of greater than 25kg/m2 for levonorgestrel and a BMI of greater than 30kg/m2 for ulipristal.

Nausea and vomiting may be more likely to occur following the administration of combination OTC tablets —the Yuzpe method — when used for EC, compared with ulipristal and levonorgestrel. Additionally, drug-drug interactions could potentially interfere with EC effectiveness, most notably hepatic enzyme CYP3A4 inducers such as rifampin, phenytoin, griseofulvin, topiramate, carbamazepine, felbamate and barbiturates.

Because the amount of time following unprotected sexual activity is a significant variable affecting oral EC product effectiveness, access and the ability to obtain an oral EC product are important factors to consider. In a recent study in Pediatrics, Wilkinson and colleagues, posing as 17-year-old “mystery callers,” surveyed 979 pharmacies in five U.S. cities in 2015 for levonorgestrel availability and accessibility. Among these pharmacies, 83% (827/979) indicated that levonorgestrel was available; however, 81 pharmacies (8.3%) informed the caller that levonorgestrel was not obtainable due to the caller’s age, whereas 474 pharmacies (48.4%) incorrectly stated that levonorgestrel was not available without a prescription at any age. These findings echo data from a similar study conducted by the researchers in 2012.

Other studies conducted following the 2013 removal of age restriction for levonorgestrel have surveyed pharmacies and demonstrated similar findings, indicating potential limited access to levonorgestrel for young women, as well as inaccurate information regarding product accessibility and availability, including limited or no availability for patients aged younger than 17 years without proof of identification or age.

Access difficulties encountered in these studies included product storage behind the pharmacy counter (thus requiring the patient to ask pharmacy staff to purchase) or limited OTC availability (on store shelving, but stored in locked enclosures). A common reason offered by pharmacies for storing levonorgestrel-containing EC products (approximately $30-$40) behind the pharmacy counter or in locked containers is theft prevention. Limited or difficult access and availability may significantly inhibit or even prevent nervous or anxious young women or men in need of EC from obtaining an effective orally administered product.

Selecting emergency contraceptives

Orally administered EC products containing levonorgestrel or ulipristal are effective and easily administered as a one-tablet dose. Although levonorgestrel-containing products are available without age restriction or health care provider prescription, ulipristal acetate — although potentially more effective than levonorgestrel — is limited by the requirement for a prescription from a health care provider.

Recent regulatory changes for levonorgestrel have reduced access barriers of age and proof of identification, and have increased OTC availability; however, not all pharmacies may be aware of these changes, or adhere to them. Because theft is a valid concern, many pharmacies store OTC EC products behind the pharmacy counter, requiring the patient to ask for its purchase. When stored in this manner, it is incumbent upon the pharmacy staff to sell and dispense the product in a convenient and confidential manner.

Sexually active women not planning a pregnancy can benefit from health care providers discussing the availability, role, and use of orally administered EC products for potential future needs. EC products, however, should not be used as a routine form of contraception. Aside from orally administered EC products, insertion of a copper-bearing intrauterine device remains an additional (and most effective) EC choice, although their use is limited by availability, insertion procedure requirement and potential cost.

In 2011, approximately 45% of the more than 6 million annual pregnancies in the United States were unintended, according to a study by Finer and colleagues in The New England Journal of Medicine. Among teens aged 15 to 19 years, approximately 6% become pregnant each year, with more than 80% of these pregnancies unplanned.

Although numerous forms of highly effective planned contraception are available, each of these methods entails potential limitations, including adherence, cost, and availability and access, among others. In the event of failed contraception due to inappropriate contraceptive product use, lack of use of a contraceptive product or sexual assault, emergency contraception (EC) products can provide an effective alternative to prevent unintended pregnancy.

Edward A. Bell

Of the three orally administered forms of EC currently available in the U.S., levonorgestrel — the active enantiomer of the progestogen norgestrel — is likely the most well-known to health care providers. Contained in Plan B One-Step (Teva Pharmaceuticals) as a single 1.5-mg tablet, levonorgestrel is available over the counter (OTC) without any age restrictions. A second form of EC is Ella (ulipristal acetate, Afaxys), in a single 30-mg tablet, which is available only by prescription.

Lastly, the Yuzpe method — named for Canadian gynecologist, Albert Yuzpe, MD, MSc — is a two-dose EC regimen employing any number of different combination estrogen/progestogen oral contraceptive tablet products that yield a dose of 100 µg of ethinyl estradiol plus 500 µg levonorgestrel, with a second dose given 12 hours later. For example, the oral contraceptive product Amethyst (Actavis Pharma) contains 20 µg of ethinyl estradiol and 90 µg of levonorgestrel per tablet; therefore, six tablets of Amethyst provides a dose of 120 µg of ethinyl estradiol and 540 µg of levonorgestrel (with a second dose given 12 hours later), using the Yuzpe method.

However, health care providers should note that some oral contraceptive products contain norgestrel as the progestogen product, and because norgestrel is a racemic mixture, a dose of 1,000 µg must be used to provide 500 µg of levonorgestrel. For example, Lo/Ovral (Wyeth Pharmaceuticals) contains 50 µg of ethinyl estradiol and 500 µg of norgestrel (equivalent to 250 µg of levonorgestrel) per tablet. Two tablets of Lo/Ovral, with a second dose repeated in 12 hours, provides a necessary Yuzpe method EC dose.

Shifting regulations

There have been significant changes in the regulatory and product availability for EC pharmacotherapies over the past 5 to 10 years. Following several years of turbulent political debate between medical organizations and social conservative groups, in 2006, the FDA approved levonorgestrel for OTC use for patients aged 18 years or older. The FDA would eventually eliminate this age limit and the need for a prescription, in 2013, to allow the sale of Plan B One-Step; 3 years later, prescription and age restrictions were likewise removed from generic levonorgestrel products as well.

Although all three orally administered EC products are effective if used within 120 hours of unprotected sex, some differences remain in efficacy and risk factors. Comparative controlled studies have demonstrated that the most effective EC product is ulipristal, with pregnancy failure rates of 0.9% to 2.1%, followed by levonorgestrel with pregnancy failure rates of 0.6% to 3.1%. The Yuzpe method is least effective. Although it can also be relied upon to provide effective EC when dosed and administered appropriately, it should be used only if levonorgestrel or ulipristal are not available.

Prior studies have indicated that efficacy does not decline within the 120-hour period for ulipristal, but evidence suggests efficacy may decline for levonorgestrel. No evidence exists to document efficacy for orally administered EC products administered after 120 hours following unprotected sex; EC products function to delay or inhibit ovulation as the primary mechanism to prevent pregnancy. Although limited and equivocal, some studies have indicated that efficacy may be reduced in women with a BMI of greater than 25kg/m2 for levonorgestrel and a BMI of greater than 30kg/m2 for ulipristal.

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Nausea and vomiting may be more likely to occur following the administration of combination OTC tablets —the Yuzpe method — when used for EC, compared with ulipristal and levonorgestrel. Additionally, drug-drug interactions could potentially interfere with EC effectiveness, most notably hepatic enzyme CYP3A4 inducers such as rifampin, phenytoin, griseofulvin, topiramate, carbamazepine, felbamate and barbiturates.

Because the amount of time following unprotected sexual activity is a significant variable affecting oral EC product effectiveness, access and the ability to obtain an oral EC product are important factors to consider. In a recent study in Pediatrics, Wilkinson and colleagues, posing as 17-year-old “mystery callers,” surveyed 979 pharmacies in five U.S. cities in 2015 for levonorgestrel availability and accessibility. Among these pharmacies, 83% (827/979) indicated that levonorgestrel was available; however, 81 pharmacies (8.3%) informed the caller that levonorgestrel was not obtainable due to the caller’s age, whereas 474 pharmacies (48.4%) incorrectly stated that levonorgestrel was not available without a prescription at any age. These findings echo data from a similar study conducted by the researchers in 2012.

Other studies conducted following the 2013 removal of age restriction for levonorgestrel have surveyed pharmacies and demonstrated similar findings, indicating potential limited access to levonorgestrel for young women, as well as inaccurate information regarding product accessibility and availability, including limited or no availability for patients aged younger than 17 years without proof of identification or age.

Access difficulties encountered in these studies included product storage behind the pharmacy counter (thus requiring the patient to ask pharmacy staff to purchase) or limited OTC availability (on store shelving, but stored in locked enclosures). A common reason offered by pharmacies for storing levonorgestrel-containing EC products (approximately $30-$40) behind the pharmacy counter or in locked containers is theft prevention. Limited or difficult access and availability may significantly inhibit or even prevent nervous or anxious young women or men in need of EC from obtaining an effective orally administered product.

Selecting emergency contraceptives

Orally administered EC products containing levonorgestrel or ulipristal are effective and easily administered as a one-tablet dose. Although levonorgestrel-containing products are available without age restriction or health care provider prescription, ulipristal acetate — although potentially more effective than levonorgestrel — is limited by the requirement for a prescription from a health care provider.

Recent regulatory changes for levonorgestrel have reduced access barriers of age and proof of identification, and have increased OTC availability; however, not all pharmacies may be aware of these changes, or adhere to them. Because theft is a valid concern, many pharmacies store OTC EC products behind the pharmacy counter, requiring the patient to ask for its purchase. When stored in this manner, it is incumbent upon the pharmacy staff to sell and dispense the product in a convenient and confidential manner.

Sexually active women not planning a pregnancy can benefit from health care providers discussing the availability, role, and use of orally administered EC products for potential future needs. EC products, however, should not be used as a routine form of contraception. Aside from orally administered EC products, insertion of a copper-bearing intrauterine device remains an additional (and most effective) EC choice, although their use is limited by availability, insertion procedure requirement and potential cost.