American Journal of Obstetrics and Gynecology (2004) 191, 1158e63 Tolerability of levonorgestrel emergency contraceptionin adolescents Cynthia C. Harper, PhD,a,* Corinne H. Rocca, MPH,a Philip D. Darney, MD, MSc,aHelena von Hertzen, MD, DDS,b Tina R. Raine, MD, MPHa Center for Reproductive Health Research and Policy, Department of Obstetrics, Gynecology, and ReproductiveSciences, School of Medicine, University of California, San Francisco, Calif, a and Department of Reproductive Healthand Research, World Health Organization, Geneva, Switzerland b Received for publication December 17, 2003; revised May 1, 2004; accepted May 5, 2004 –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– Objective: We evaluated the tolerability of emergency contraception in adolescents.
Study design: In this descriptive study, 1 0.75 mg levonorgestrel tablet was administered to 52 females aged 13-16 with instructions to take the second tablet 12 hours later (unprotected inter- course was not an entry requirement). Participants kept diaries of side effects and menstrual pat- terns. We assessed correct use, side effects caused by treatment, and impact on menstrual cycle.
Results: Virtually all participants used the drug correctly, with no serious adverse events. Minorexpected side effects occurred, including nausea, fatigue, and vomiting. There was no difference inreporting of side effects by age. Adolescents’ mean duration of menses was comparable pre- andpost-treatment (5.3 vs 5.0 days; P= .146), and onset of menses was within the expected range.
Ninety percent of participants reported they would recommend emergency contraception toa friend or relative if needed.
Conclusion: Adolescents tolerated the medication well, experiencing transient side effects.
Ó 2004 Elsevier Inc. All rights reserved.
––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– In 1999, the United States Food and Drug Adminis- correct use of the treatmentMoreover, levonorgestrel tration (FDA) approved 0.75 mg levonorgestrel Plan BÒ was found to have an acceptable side effect profile, with (Gedeon Richter, Ltd, Budapest, Hungary) tablets for 23% of participants reporting nausea and 5.6% vomit- use postcoitally as an emergency contraceptive. The ing, lower levels than with the standard Yuzpe regimen safety and efficacy of emergency contraception (EC) is (ethinyloestradiol 100 mg plus levonorgestrel 0.5 mg or well established for adults. In the World Health Organi- dl-norgestrel 1.0 mg, repeated 12 hours later). Subse- zation (WHO) Task Force study of levonorgestrel EC, quent studies of women in various countries also 89% of expected pregnancies were prevented with showed levonorgestrel EC to be well tolerated.
While young age is associated with greater awareness of emergency contraception, use of the method is morecommon among adult women than adolescents.We * Reprint requests: Cynthia C. Harper, PhD, UCSF Box 0744, have scant data on the tolerability and acceptability of 3333 California Street, Ste. 335, San Francisco, CA, 94143-0744.
the method to adolescents. As with other hormonal 0002-9378/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.ajog.2004.05.011 contraceptives, current FDA labeling of Plan BÒ is not Research. Procedures were in accordance with the ethical specific with respect to use in girls aged 16 years and standards for human experimentation established by the younger. If the FDA moves to switch Plan BÒ emer- Declaration of Helsinki of 1975, revised in 1983.
gency contraception to over-the-counter status, adoles- Research assistants administered study procedures cents as well as adults will be able to use it without at the clinic site. Participants were given the first dose provider supervision. Clinical trials of contraceptives of emergency contraception in the clinic, and were in- in the US include adults only, a minority of whom are structed to take the second dose in 12 hours. They were between the ages of 18 and 19 years. While enrolling given diary cards and were asked to record the date and adolescents in clinical trials is difficult, there is a growing time of the second dose, and to keep a daily record of recognition of the need to address the paucity of data in any bleeding and side effects until the follow-up visit 3 weeks after enrollment. The diary was collected at the One study on levonorgestrel implants showed that follow-up visit. The format of the diary card, as well tolerance of side effects was comparable among adoles- as the methods, including product, dose, and route of cents and adults.Studies of low-dose progestin-only administration were as similar as possible to those in pills for long-term contraception have shown no differ- the levonorgestrel arm of the large WHO multicenter ences in safety or efficacy among adolescents aged 16 that evaluated side effects. Unlike the WHO trial, years and older compared with adultsHowever, there which compared the efficacy and safety of different is no information on the higher doses of progestins used emergency contraceptive agents and regimens, this trial examined only the current FDA-approved Plan B regi- The primary objective of this study was to evaluate men of 2 doses 12 hours apart. The participants in this the tolerability of levonorgestrel emergency contracep- study had not experienced unprotected intercourse dur- tion (Plan BÒ) in adolescent females. Specifically, the ing the present cycle, while the participants in the WHO study aimed to characterize the side effects profile, assess trial were seeking emergency contraception because of correct use of the method, and ascertain the impact on need after an act of unprotected intercourse.
the menstrual cycle in a sample of young adolescents.
Participants who had not resumed menses at follow- up returned for an additional visit. The study period wasthus from 3 to 5 weeks, depending on regular menstrual cycle variation and timing of menses subsequent to dos-ing. Research assistants took medical histories at enroll- ment, and administered short interviews at enrollmentand follow-up that included items on the participant’s This study was a single-center, open-label observational experience using emergency contraception. Participants trial. Two 0.75 mg Plan BÒ levonorgestrel tablets were ad- were given $50 at enrollment and $50 at follow-up; if re- ministered orally to adolescent females recruited at a pub- quired to return for a second follow-up visit, partici- licly funded San Francisco family planning clinic and through flyers at community centers. Inclusion criteriafor the study were: females aged 12 to 16 years who hadreached menarche; good health based on physical exami-nation, medical history, urine analysis, and laboratory evaluation; normal menstrual cycles for the previous 6cycles, varying in length from 21 to 35 days; no unpro- Correct use of the medication was measured by self- tected intercourse during the current cycle (to avoid very reports of whether participants followed instructions early pregnancy); willing to abstain from intercourse or to to ingest the second dose, and whether they had any use condoms for the study duration; no sex steroid use (in- problems following directions. We used diary data to cluding hormonal contraception) in the past 2 months.
measure the frequency (in days) of side effects, including Exclusion criteria were pregnancy or breastfeeding, hy- nausea, vomiting, headache, dizziness, fatigue, breast persensitivity to levonorgestrel or other progestins, use tenderness, lower abdominal pain, and diarrhea. To as- of an investigational drug within 30 days, history of emo- sess impact on menses, we measured the length of men- tional or psychiatric disorders or use of psychotropic ses before and after treatment (ie, mean duration of agents, evidence or admission of illicit drug or alcohol menstrual flow), and also measured the time until men- abuse. Research assistants told potential participants ses after administration of the treatment compared and their parents that the study was looking at emergency with the anticipated date (calculated from date of last contraception and side effects and menstrual bleeding in menstrual period and cycle length). As a general accept- girls aged 12 to 16 years. Parental consent was required ability measure, we also recorded whether participants for participation. The study was approved by the Univer- would recommend emergency contraception to a friend sity of California, San Francisco, Committee on Human or relative if needed (yes, no, not sure).
. Participants ranged in age from 13 to 16 years, Summary of sample characteristics (n = 52) with a mean age of 15.5 years. Most participants were racial/ethnic minorities; 61% were African American, 19% Latina, 15% multiracial, and 4% white.
Ninety-eight percent of participants (51/52) reported taking the second dose of Plan BÒ as instructed.
Ninety-four percent (49/52) reported no problems in fol- lowing directions. Because correct use was uniformly high, we could not test variation in correct use by age.
In , we compared symptoms reported during the first week (days 1 to 7) with symptoms reported during the second week (days 8 to 14). Nausea was reported in the first week by 38.5% of participants and vomiting by11.5%. Several other side effects were also commonly re- * Only participants who have had sexual intercourse (n = 36).
ported. Reports of some symptoms, including nausea(P = .001), fatigue (P = .002), headache (P = .004), and diarrhea (P = .004) were significantly higher duringthe first week. However, for others, reports were not sig- To analyze side effects caused by treatment, we com- nificantly higher in the first week than they were in the pared side effects reported by participants during second, including vomiting (P = .160), dizziness (P = the first week (days 1 to 7) after drug administration .130), breast tenderness (P = .582), and lower abdominal to those reported during the second week (days 8 to pain (P = .088). Kruskal-Wallis tests showed no differ- 14), when virtually no levonorgestrel was present in ence by age in any of the reported side effects ).
the serum; a pharmacokinetic study showed the meanhalf life of levonorgestrel in adolescents to be 21 hours.
We used two-sided t tests to compare the number ofdaily reports of each side effect during the first week There was no difference in the mean duration of (days 1 to 7) with the number of daily reports of the menses for the adolescents before and after treatment same side effect during the second week (days 8 to 14).
In the last menstrual period before enroll- We used two-sided t tests to assess any difference ment, the mean duration of menses was 5.0 days, and in menstrual flow caused by treatment: menstrual flow at after treatment the mean duration of menses was last menstrual period (LMP) before enrollment was com- 5.3 days (P = .146). Eight percent experienced a delay pared with menstrual flow after treatment. Kruskal- in return to menses over 7 days, 62.5% had a return Wallis tests were used to detect age differences in return to menses within 7 days of the anticipated date, and to menses within the adolescent sample, as well as any 29% an early onset of more than 7 days. Kruskal-Wallis differences in correct use, side effects, or acceptability.
tests showed no differences by age in return to menses Significance is reported at the .05 level. Stata 6.0 (P = .104) or in duration of flow compared with normal (College Station, Tex) was used for the analysis.
(P = .313). One participant had unprotected intercourseand had an intrauterine pregnancy.
Recommendation of emergency contraception A total of 60 participants were enrolled in the study. Six Ninety percent (47/52) of participants reported that they participants enrolled were ineligible; 1 was younger than would recommend emergency contraception to a friend 12 years old (11.6 years), and 5 had taken levonorgestrel or relative if needed. All others responded that they were within 2 months of recruitment. Two participants, aged not sure. Kruskal-Wallis tests showed no difference by 16 years, were lost to follow-up. We analyzed data from age (P = 0.756) in whether a participant would recom- the 52 eligible participants who completed the study.
mend EC or was unsure about it. There were no serious Summary baseline characteristics are presented in Diary reports of symptoms by week (n = 52) * Symptoms in days 8 to 14 when levonorgestrel no longer biologically available.
y Paired t test comparing number of days symptom reported in weeks 1 and 2.
z P % .010.
Differences in reports of symptoms (days 1 to 7) by (n = 48), LMP at follow-up,as compared with expected * Numbers vary because of the following: 2 participants did not Concerns about the side effects of hormonal contracep- begin menses by follow-up visit; 1 became pregnant during study; 2 tion are common among the general public.Beliefs were still bleeding at follow-up visit; 1 had missing data on menses.
about negative side effects, even when false, can stopadolescents from using hormonal contraception.How-ever, this age group stands to benefit the most from use levels of vomiting reported. Some of the side effects, of the product, and to lose the most from misconcep- such as nausea, headaches, and fatigue are reported at tions because almost 80% of adolescent pregnancies higher levels by this adolescent sample, while others, in- are unintended.This study found that adolescents re- cluding abdominal pain and breast tenderness, are at ported minor and transient side effects, similar to those similar levels. However, comparisons should be inter- reported in previous adult trials, including nausea preted with caution because of many differences in the and vomiting. However, the adolescents tended to re- samples other than age, including need for emergency port many symptoms even when they no longer had lev- contraception at enrollment and different nationalities onorgestrel in their serum. For nausea or headaches, and racial/ethnic compositions. International studies on common and somewhat subjective symptoms, there emergency contraception as well as other medications were significantly higher reports during the first week, have shown that women of different nationalities and but for vomiting, the least subjective symptom, there races/ethnicities experience and report symptoms differ- were no significant differences in levels reported. Vomit- entlyThere is some evidence that women in deve- ing is an important symptom because of its potential im- loped countries report more side effects than women in developing couHowever, all reported side effects A comparison between the side effects reported in were well within the range of what adult trials have this study with the data from adults in the large inter- shown and present no serious health risks. A random- national WHO trialso shows little difference in the ized, controlled placebo trial would be necessary to clarify any differences in adolescent users and adults.
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20. Raine T, Harper C, Leon K, Darney P. Emergency contraception: We gratefully acknowledge the William and Flora advance provision in a young, high-risk clinic population. Obstet Hewlett Foundation for their financial support.
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