Levonorgestrel-Only Dosing Strategies for Emergency Contraception
Levonorgestrel-Only Dosing Strategies for Emergency Contraception
The United States Food and Drug Administration-approved progestin-only dosing strategy for emergency contraception is levonorgestrel 0.75 mg taken as soon as possible within 72 hours of unprotected intercourse, with a second 0.75-mg dose taken 12 hours later. However, different dosing strategies have been studied and promoted by various organizations. The American College of Obstetricians and Gynecologists recommends a single dose of levonorgestrel 1.5 mg for emergency contraception as one option. As another option, they recommend two doses of levonorgestrel 0.75 mg may be effective when taken 12-24 hours apart. We performed a search of MEDLINE and International Pharmaceutical Abstracts from 1967-2006 to evaluate and describe the existing pharmacokinetic and patient outcome data regarding administration of levonorgestrel as a 1.5-mg single dose or two 0.75-mg doses taken 12 or 24 hours apart. Additional studies were identified from the bibliographies of the selected literature. Several pertinent articles were identified. All of the studies demonstrated that emergency contraception effectively prevented pregnancy. In addition, evidence supports the safety and efficacy of a single dose of levonorgestrel 1.5 mg for emergency contraception. Furthermore, when two doses of levonorgestrel 0.75 mg are administered, the second dose can confidently be taken 12-24 hours after the first without compromising efficacy. Understanding the evidence that supports the different emergency contraception dosing strategies is critical for clinicians, and especially pharmacists, who have interactive roles in dispensing emergency contraception.
Emergency contraception, or postcoital contraception, is administered to prevent pregnancy after unprotected or inadequately protected sexual intercourse. Failure to use any form of contraception, or contraceptive failure (e.g., one or more missed doses of oral contraceptive, broken condom) are the two most common situations leading to the need for emergency contraception. The United States Food and Drug Administration (FDA) approved levonorgestrel for emergency contraception in July 1999. The currently approved progestin-only treatment is two doses of levonorgestrel 0.75 mg (Plan B; Barr Pharmaceuticals, Woodcliff Lake, NJ); the first dose should be taken as soon as possible within 72 hours of unprotected intercourse, with the second dose taken 12 hours later. Although high doses of combined estrogen and progestin oral contraceptives have been used for decades as emergency contraception (the Yuzpe regimen), these regimens cause more adverse effects than the progestin-only regimen.
Efficacy, safety, and tolerability have made levonorgestrel-only emergency contraception a common treatment for preventing pregnancies in the United States. Based on six studies involving over 8000 women, various dosing regimens of levonorgestrel-only emergency contraception reduced the chance of pregnancy by 60-94%; efficacy was greatest when treatment was started as soon as possible. Moreover, efficacy of levonorgestrel-only emergency contraception is superior to that of combined estrogen and progestin emergency contraception.
Levonorgestrel-only emergency contraception was recommended for approval as a nonprescription drug in 2003 by a combined panel of the FDA's Advisory Committee on Reproductive Health Drugs and its Advisory Committee on Nonprescription Drugs. This recommendation was based on levonorgestrel's high efficacy, minimal adverse effects, and few contraindications, and on studies demonstrating that consumers could appropriately take the drug based on a prototype over-the-counter label. It is now available as an over-the-counter option for women aged 18 and older; it is available by prescription only for women younger than 18 years. Levonorgestrel-only emergency contraception is associated with significantly less nausea and vomiting than combination treatment. Nausea and vomiting occur in 18% and 4%, respectively, of women taking levonorgestrel only, and in 43% and 16% of those receiving combination treatment.
Emergency contraception can prevent pregnancy within the 5 days between intercourse and implantation of a fertilized egg by delaying or inhibiting ovulation. However, with an efficacy rate up to 94%, this probably is not the only method of action. The entire mechanism of action of levonorgestrel emergency contraception has not been fully elucidated and likely varies according to the days of the menstrual cycle on which intercourse occurs and emergency contraception is administered. Initial data documented histologic and biochemical changes in the endometrium that could affect implantation. However, subsequent data have not supported these findings, and endometrial changes do not appear sufficient to prevent implantation.
Other proposed mechanisms are thickening of cervical mucus causing trapping of sperm; impairment of corpus luteum function; alterations in the tubal transport of sperm, egg or embryo; and direct inhibition of fertilization. However, no direct clinical evidence supports these mechanisms. Emergency contraception is effective only before a fertilized egg is implanted (when pregnancy is established); it does not disrupt an existing pregnancy. One group of authors hypothesized that the minimum concentration needed to inhibit ovulation is 0.48 nmol/L. Therefore, appropriate dosing is critical to ensure prevention of pregnancy.
The 2005 American College of Obstetricians and Gynecologists (ACOG) practice bulletin concerning emergency contraception provides level A recommendations (based on good and consistent scientific evidence) for several levonorgestrel emergency contraception regimens. However, they do not concur with the current FDA-approved regimen of two doses of levonorgestrel 0.75 mg taken 12 hours apart. As one option, ACOG recommends a single levonorgestrel-only dose of 1.5 mg. As another option, they recommend that two doses of levonorgestrel 0.75 mg may be effective when taken 12-24 hours apart.
Clinicians should be aware of these dosing recommendations since levonorgestrel-only emergency contraception may be prescribed with one of these two off-label strategies. Pharmacists are actively involved in dispensing emergency contraception with and without a prescription. Pharmacists need to understand the evidence supporting these level A dosing recommendations from ACOG, especially if asked to provide levonorgestrel at a dosage not approved by the FDA for emergency contraception.
We searched MEDLINE and International Pharmaceutical Abstracts from 1967-2006 using the key terms emergency contraception, postcoital contraception, postcoital contraceptives, levonorgestrel, and single dose. We limited the search to English-language reports involving humans. Studies were selected if pharmacokinetics or patient outcomes were evaluated with alternative levonorgestrel-only emergency contraception dosing strategies. Additional studies were identified from the bibliographies of the selected literature. Several studies provided a rationale for the single-dose strategy, but only a few described a rationale for the two-dose regimen taken 12-24 hours apart.
Abstract and Introduction
Abstract
The United States Food and Drug Administration-approved progestin-only dosing strategy for emergency contraception is levonorgestrel 0.75 mg taken as soon as possible within 72 hours of unprotected intercourse, with a second 0.75-mg dose taken 12 hours later. However, different dosing strategies have been studied and promoted by various organizations. The American College of Obstetricians and Gynecologists recommends a single dose of levonorgestrel 1.5 mg for emergency contraception as one option. As another option, they recommend two doses of levonorgestrel 0.75 mg may be effective when taken 12-24 hours apart. We performed a search of MEDLINE and International Pharmaceutical Abstracts from 1967-2006 to evaluate and describe the existing pharmacokinetic and patient outcome data regarding administration of levonorgestrel as a 1.5-mg single dose or two 0.75-mg doses taken 12 or 24 hours apart. Additional studies were identified from the bibliographies of the selected literature. Several pertinent articles were identified. All of the studies demonstrated that emergency contraception effectively prevented pregnancy. In addition, evidence supports the safety and efficacy of a single dose of levonorgestrel 1.5 mg for emergency contraception. Furthermore, when two doses of levonorgestrel 0.75 mg are administered, the second dose can confidently be taken 12-24 hours after the first without compromising efficacy. Understanding the evidence that supports the different emergency contraception dosing strategies is critical for clinicians, and especially pharmacists, who have interactive roles in dispensing emergency contraception.
Introduction
Emergency contraception, or postcoital contraception, is administered to prevent pregnancy after unprotected or inadequately protected sexual intercourse. Failure to use any form of contraception, or contraceptive failure (e.g., one or more missed doses of oral contraceptive, broken condom) are the two most common situations leading to the need for emergency contraception. The United States Food and Drug Administration (FDA) approved levonorgestrel for emergency contraception in July 1999. The currently approved progestin-only treatment is two doses of levonorgestrel 0.75 mg (Plan B; Barr Pharmaceuticals, Woodcliff Lake, NJ); the first dose should be taken as soon as possible within 72 hours of unprotected intercourse, with the second dose taken 12 hours later. Although high doses of combined estrogen and progestin oral contraceptives have been used for decades as emergency contraception (the Yuzpe regimen), these regimens cause more adverse effects than the progestin-only regimen.
Efficacy, safety, and tolerability have made levonorgestrel-only emergency contraception a common treatment for preventing pregnancies in the United States. Based on six studies involving over 8000 women, various dosing regimens of levonorgestrel-only emergency contraception reduced the chance of pregnancy by 60-94%; efficacy was greatest when treatment was started as soon as possible. Moreover, efficacy of levonorgestrel-only emergency contraception is superior to that of combined estrogen and progestin emergency contraception.
Levonorgestrel-only emergency contraception was recommended for approval as a nonprescription drug in 2003 by a combined panel of the FDA's Advisory Committee on Reproductive Health Drugs and its Advisory Committee on Nonprescription Drugs. This recommendation was based on levonorgestrel's high efficacy, minimal adverse effects, and few contraindications, and on studies demonstrating that consumers could appropriately take the drug based on a prototype over-the-counter label. It is now available as an over-the-counter option for women aged 18 and older; it is available by prescription only for women younger than 18 years. Levonorgestrel-only emergency contraception is associated with significantly less nausea and vomiting than combination treatment. Nausea and vomiting occur in 18% and 4%, respectively, of women taking levonorgestrel only, and in 43% and 16% of those receiving combination treatment.
Emergency contraception can prevent pregnancy within the 5 days between intercourse and implantation of a fertilized egg by delaying or inhibiting ovulation. However, with an efficacy rate up to 94%, this probably is not the only method of action. The entire mechanism of action of levonorgestrel emergency contraception has not been fully elucidated and likely varies according to the days of the menstrual cycle on which intercourse occurs and emergency contraception is administered. Initial data documented histologic and biochemical changes in the endometrium that could affect implantation. However, subsequent data have not supported these findings, and endometrial changes do not appear sufficient to prevent implantation.
Other proposed mechanisms are thickening of cervical mucus causing trapping of sperm; impairment of corpus luteum function; alterations in the tubal transport of sperm, egg or embryo; and direct inhibition of fertilization. However, no direct clinical evidence supports these mechanisms. Emergency contraception is effective only before a fertilized egg is implanted (when pregnancy is established); it does not disrupt an existing pregnancy. One group of authors hypothesized that the minimum concentration needed to inhibit ovulation is 0.48 nmol/L. Therefore, appropriate dosing is critical to ensure prevention of pregnancy.
The 2005 American College of Obstetricians and Gynecologists (ACOG) practice bulletin concerning emergency contraception provides level A recommendations (based on good and consistent scientific evidence) for several levonorgestrel emergency contraception regimens. However, they do not concur with the current FDA-approved regimen of two doses of levonorgestrel 0.75 mg taken 12 hours apart. As one option, ACOG recommends a single levonorgestrel-only dose of 1.5 mg. As another option, they recommend that two doses of levonorgestrel 0.75 mg may be effective when taken 12-24 hours apart.
Clinicians should be aware of these dosing recommendations since levonorgestrel-only emergency contraception may be prescribed with one of these two off-label strategies. Pharmacists are actively involved in dispensing emergency contraception with and without a prescription. Pharmacists need to understand the evidence supporting these level A dosing recommendations from ACOG, especially if asked to provide levonorgestrel at a dosage not approved by the FDA for emergency contraception.
We searched MEDLINE and International Pharmaceutical Abstracts from 1967-2006 using the key terms emergency contraception, postcoital contraception, postcoital contraceptives, levonorgestrel, and single dose. We limited the search to English-language reports involving humans. Studies were selected if pharmacokinetics or patient outcomes were evaluated with alternative levonorgestrel-only emergency contraception dosing strategies. Additional studies were identified from the bibliographies of the selected literature. Several studies provided a rationale for the single-dose strategy, but only a few described a rationale for the two-dose regimen taken 12-24 hours apart.
Source...