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WYETH_CE_Contraceptive_0506_E 4/27/06 9:35 AM Page 1 A FREE CONTINUING EDUCATION LESSON OBJECTIVES Upon successful completion of this lesson, the pharmacist will: 1. understand the differences between continuous combined oral contraceptives and cyclic or extended cycle combined oral contraceptives. 2. be familiar with the unique benefits of combined oral contraceptives taken continuously. 3. understand which patients might benefit from continuous use of a combined oral contraceptive. 4. understand how continuous combined oral contraceptives can improve management of conditions affected by hormonal fluctuations such as endometriosis and menstrual migraines. 5. be familiar with side effects that can occur with continuous combined oral contraceptives. 6. be able to effectively counsel patients on continuous combined oral contraceptives. INSTRUCTIONS 1. After carefully reading this lesson, study each question and select the one answer you believe to be correct. Circle the appropriate letter on the attached reply card. 2. To pass this lesson, a grade of 70% (14 out of 20) is required. If you pass, your CEU(s) will be recorded with the relevant provincial authority(ies). (Note: some provinces require individual pharmacists to notify them.) ANSWERING OPTIONS A. For immediate results, answer online at www.pharmacygateway.ca. B. Mail or fax the printed answer card to (416) 764-3937. Your reply card will be marked and you will be advised of your results within six to eight weeks in a letter from Rogers Publishing. THIS FREE LESSON Continuous Use of Combined Oral Contraceptives By Jodi Wilkie, BScPharm Jodi Wilkie works in retail pharmacy at Canada Safeway in Edmonton. She also works for the Caritas Health Group in the Women's Wellness Program Menopause Clinic where she sees patients one-on-one and works closely with physicians to maximize patient-care outcomes. The author, expert reviewers and Pharmacy Practice magazine have each declared that there is no real or potential conflict of interest with the sponsor of this lesson. INTRODUCTION Hormonal contraceptive pills containing synthetic estrogen and progestin have been available since the 1960’s and continue to be a very popular reversible method of birth control. In Statistics Canada’s 1996/97 National Population Health Survey, 18% of women aged 15 to 49 reported using combined oral contraceptives (COCs).1 In general, COCs are safe, effective and well-tolerated by women across the reproductive age span. Over the years, doses and types of hormones found in COCs have changed. Initially, estrogen doses were relatively high. Most COCs now contain 35 µg of ethinyl estradiol or less. A number of different progestins are found in currently available COCs. Recently, two combined hormonal contraceptives with novel delivery methods became available to Canadian women—a transdermal patch and a vaginal ring. Although doses, components and delivery methods have changed, the typical COC regimen has remained relatively constant. IS APPROVED FOR 1.5 CE UNITS Women usually take estrogen and progestin for 21 consecutive days, followed by a 7-day hormone-free interval. It is during this 7-day interval that withdrawal uterine bleeding may occur. When COCs were first developed, the typical 21/7 regimen was designed arbitrarily to mimic a regular 28-day menstrual cycle. It was thought that COCs would be considered more natural and appealing to women and their physicians if regular monthly bleeding occured.2 At the time, no consideration was given to alternative regimens. The withdrawal bleeding that occurs with a standard COC regimen is not biological, but is induced by the drop in hormone levels when active tablets are stopped.3 It is iatrogenic. It does not serve a medical purpose, but it may help to reassure a woman that she is not pregnant. Occasionally women and their physicians manipulate this standard regimen for the purpose of convenience. A woman on COCs whose menstrual period is due during a scheduled vacation or SUPPORTED BY AN EDUCATIONAL GRANT FROM Approved for 1.5 CE units by the Canadian Council on Continuing Education in Pharmacy. File #388-0306. May 2006 | Answer online at www.pharmacygateway.ca Continuous Use of Combined Oral Contraceptives | 1 WYETH_CE_Contraceptive_0506_E 4/27/06 event may take two packages of monophasic COC in a row without a pill-free interval in order to postpone menstruation. Seventy percent of the providers in one survey had prescribed COCs to delay or stop a patient’s periods for a certain amount of time.4 Different hormonal contraception regimens have been studied. The duration of active tablets has been extended for two or more cycles followed by a 7day or shorter pill-free interval.5 In the United States, two hormonal contraceptive products with unique regimens are available. With Mircette®, ethinyl estradiol 20 µg and desogestrel 150 µg are taken for 21 days, followed by a 2-day pill-free interval and then 5 days of ethinyl estradiol 10 µg. Another product, Seasonale®, provides 84 days of ethinyl estradiol 30 µg and levonorgestrel 150 µg followed by a 7-day pill-free interval. With Seasonale’s extended cycle regimen, withdrawal bleeding occurs 4 times per year. This product may be available in Canada in the future. Pending approval by Health Canada, a novel COC will be available to Canadian women. The new product, called Anya®, will contain 20 µg of ethinyl estradiol and 90 µg of levonorgestrel per tablet and will be taken on a continuous daily basis without a pill-free interval. Pills will be available in packages containing a 28-day supply of medication. A study conducted in over 2,000 women for 12 months has shown this regimen to be safe, effective and well-tolerated.6 The purpose of a continuous regimen, besides preventing pregnancy, is to suppress menstruation. Women taking a COC continuously may go without a period for a prolonged length of time. During this time, hormone levels will stay constant. Fluctuation of hormone levels, which is a regular occurrence within a natural menstrual cycle and with standard 21/7 combined hormonal contraceptive methods, will not occur. Menstrual suppression and stabilization of hormone levels has the potential to be beneficial for many women. Continuous use of a COC without a hormone-free break may be a good option for women who experience severe symptoms during 2 9:35 AM Page 2 TABLE 1: Percentage of current COC users (N=193) experiencing hormone withdrawal symptoms during active pills days vs. during the hormone-free interval of one cycle of use8 Active pill days (%) Hormone-free interval (%) Pelvic pain 21 70 Headaches 53 70 Use of pain medication 43 69 Bloating or swelling 19 58 Breast tenderness 16 38 their menstrual period each month or who have conditions that are aggravated by hormone fluctuations, such as endometriosis or menstrual migraines. Alternatively, some women may choose a continuous regimen mainly for convenience. HORMONE WITHDRAWAL SYMPTOMS With a standard 21/7 COC regimen, many women experience symptoms associated with withdrawal bleeding. Menstrual symptoms such as sore breasts, menstrual cramps and headaches may be a mild nuisance for some women. For others, symptoms may be more severe resulting in reduced productivity because of school or work time missed. Symptoms may contribute to problems with COC compliance leading to discontinuation and unintended pregnancy.7 A group of researchers documented the timing, frequency and severity of hormone-related symptoms in COC users during active pills and the pill-free interval of a standard regimen.8 Women monitored and recorded pelvic pain, bleeding, headaches, analgesic use, nausea or vomiting, bloating or swelling and breast tenderness throughout the course of the study. New COC users recorded symptoms for three full cycles and current COC users recorded symptoms over two full cycles. The researchers determined that in almost all current COC users symptoms were more frequent (P<0.001) during the 7-day hormonefree interval than during active pills. (See Table 1 for results.) In new COC users, similar results were seen in the second and third cycles of COC. In their first COC cycle, incidence of headaches and breast tender- | Continuous Use of Combined Oral Contraceptives ness in new COC users was similar during active pills and during the first hormone-free interval. Interestingly in this study, breast tenderness and bloating or swelling began to increase in the week prior, and worsened during the hormone-free interval. The researchers theorized that estradiol levels began increasing during the hormone-free interval, peaked during the second week of active pills and decreased in the third week of active pills, thereby bringing on these symptoms prior to the next hormone-free interval. Because hormone levels are maintained for a prolonged length of time with an extended or continuous COC regimen, hormone withdrawal symptoms may be reduced or eliminated. In a prospective, open clinical trial, 50 women with complaints experienced during the hormone-free interval of their current COCs were permitted to extend their active tablets to see whether frequency of these symptoms would be reduced.9 These women experienced dysmenorrhea (painful menstruation), menorrhagia (heavy menstruation), premenstrual-type symptoms and menstrual migraines with the standard 21/7 regimen. Of 37 patients who continued to extend their active tablets to 6, 9 or 12 weeks, all reported that doing so delayed the onset and decreased the severity of their reported menstrual complaints. Thirteen patients chose not to continue with an extended regimen, mainly because of breakthrough bleeding, spotting or headaches. A one year open-label phase 3 study evaluated how continuous ethinyl estradiol 20 µg/levonorgestrel 90 µg would affect cycle-related symptoms and dysmenorrhea.10 Thirty-six women recorded occurrence and severity of cycle-related Answer online at www.pharmacygateway.ca | May 2006 WYETH_CE_Contraceptive_0506_E 4/27/06 symptoms using the Penn Daily Symptom Rating diary, a validated symptom diary, during a baseline cycle without the COC and during three 28day pill packages of COC. Cycle-related symptom scores decreased significantly compared to baseline during the three pill packages of study. In women with dysmenorrhea (N=259), pain scores decreased from baseline by 71% and 85% in pill packs 2 and 3 respectively. Continuous COC in this study appears to have been very effective in reducing menstrual cramps. EFFICACY OF CONTINUOUS COMBINED ORAL CONTRACEPTIVES The primary mechanism of action of hormonal contraceptives is the inhibition of ovulation. COCs suppress release of follicle stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary and prevent ovarian follicular development and ovulation. As well, cervical mucus thickens and becomes impenetrable to sperm, and the endometrial environment becomes less receptive to an ovum if fertilization occurs.11 When standard COCs are taken as prescribed, pregnancy rates are very low with less than 1 pregnancy per 100 women per year of use.12 Pregnancy rates approach 6 to 8 per 100 women per year with typical use.12 Inconsistent pill-taking time and omission of one or more pills per cycle contribute to reduced efficacy. As a large number of women occasionally miss a pill or take their pills at slightly different times of day, a hormonal contraceptive method with increased efficacy is desirable. During the 7-day pill-free interval of a standard 21/7 COC, some ovarian follicular development occurs in response to rising FSH levels, with corresponding increases in endogenous estrogen levels.13-15 If this pill-free interval is extended, more follicular growth ensues with the potential for ovulation.13 Missing pills at the end of one cycle or near the beginning of another or forgetting to restart the COC has the effect of lengthening the pill-free interval and increases the likelihood that ovulation and pregnancy could occur. If the pill-free interval is shortened or eliminated, there is less potential for follicular growth and 9:35 AM Page 3 ovulation.14,15 It is not known if this reduced follicular growth translates into fewer unintended pregnancies when a COC is used on a continuous basis. One unpublished phase 3 study of continuous ethinyl estradiol 20 µg/levonorgestrel 90 µg reported a Pearl Index of 1.6 after one year of use.6 The Pearl Index, a measurement of contraceptive effectiveness, is a statistical estimation of the number of unintended pregnancies per 100 women per year of use. A 2005 Cochrane review of six studies comparing continuous or extended cycle COCs to standard cyclic COCs concluded that risk of pregnancy did not differ between regimens except in one trial that showed fewer pregnancies in the continuous COC group.16 POTENTIAL BENEFITS OF CONTINUOUS COMBINED ORAL CONTRACEPTIVES Women take COCs for various reasons. Most often the primary reason is to reduce the risk of pregnancy. Although not specifically approved for these indications, women may use COCs for therapeutic purposes as well. By maintaining constant hormone levels, continuous administration of a COC may benefit conditions such as premenstrual syndrome, menstrual migraines, endometriosis and polycystic ovary syndrome that may be worsened by hormonal fluctuations. Premenstrual syndrome Premenstrual syndrome (PMS) is a constellation of symptoms that occurs in the luteal phase of the menstrual cycle on a recurring basis. Symptoms can be physical and psychological and may include irritability, mood swings, depression, anxiety, fatigue, breast tenderness, bloating, changes in appetite and sleep problems. These symptoms can have a negative impact on quality of life. When symptoms are so severe that they disrupt functioning in the home or workplace, the condition is termed premenstrual dysphoric disorder (PMDD). Although the exact cause is unknown, it is believed that women who suffer from PMS or PMDD have an altered sensitivity to estradiol and progesterone that interferes with serotonergic function.17 There is some evidence available May 2006 | Answer online at www.pharmacygateway.ca regarding the use of combined oral contraceptives for the relief of PMS or PMDD. In a randomized, single-blind study comparing three different kinds of COCs for PMS, all COCs had a beneficial effect on PMS symptoms compared to the pre-treatment period.18 Another COC was studied in a randomized, placebo controlled trial for its effect on PMDD.19 Improvement from baseline was noted for 22 different premenstrual symptoms. Although these studies used standard 21/7 COC regimens, there is limited data supporting the use of continuous COCs as well.10 An unpublished study presented at the 2005 Conjoint Meeting of the American Society for Reproductive Medicine and the Canadian Fertility and Andrology Society found significant improvement in premenstrual symptom scores from baseline in women with PMS during three 28-day pill packages of continuous ethinyl estradiol 20 µg/levonorgestrel 90 µg.10 Menstrual migraines Menstrual migraines are migraine headaches that occur in close proximity to a woman’s menstrual period. Within a natural menstrual cycle, they occur from two days prior to menses until three days into menses. They can also occur during the 7-day hormone-free interval of COCs. Women may also experience migraines at different times of the month in response to other triggers. It may be helpful for a woman to keep a migraine diary, charting frequency and severity of headaches, to determine if migraines are specifically menstrual. It is thought that menstrual migraines are triggered by the drop in estrogen levels that occurs prior to menstruation.20,21 Acute treatment of menstrual migraines involves triptans and/or NSAIDs, although for some women, these measures are relatively ineffective.21 Menstrual migraines are often quite severe with prolonged duration possibly because of the continued drop in estrogen levels at that time in the cycle. Pain medication or triptan may be effective temporarily, but the headache returns because the trigger is still present. Because a drop in estrogen levels contributes to menstrual migraines, maintaining constant estrogen levels for an Continuous Use of Combined Oral Contraceptives | 3 WYETH_CE_Contraceptive_0506_E 4/27/06 extended period of time with a continuous COC has potential to be a helpful preventive and therapeutic measure.21 Use of COCs in women with migraine, particularly migraine with aura, is controversial.21 Clinical practice guidelines from the Society of Obstetricians and Gynecologists of Canada list migraine with aura as an absolute contraindication to COC use.11 COCs can have unpredictable effects on migraine course. When starting on COCs, patients may experience an improvement or a worsening in migraine symptoms and occurrence. It is important for patients to monitor migraine frequency and severity and the presence and nature of an aura preceding the migraine attack. Migraine appears to be an independent risk factor for ischemic stroke, with increased risk occurring with migraine with aura.22 COCs also increase stroke risk although risk is lower for COCs containing less than 50 µg ethinyl estradiol.11 The main concern is that these individual risk factors may have a synergistic effect. It is important to consider a woman’s other stroke risk factors including age, smoking, hypertension, hypercholesterolemia and diabetes when weighing benefits and risks of hormonal contraceptive use. COCs should be discontinued in a woman who experiences an aura for the first time, a worsening of migraine aura or a worsening of migraine headaches. Endometriosis Endometriosis is a condition where endometrial tissue grows outside of the uterus. This tissue responds to hormonal stimulation the same way that the uterine endometrial tissue does, with menstrual bleeding occurring cyclically. Symptoms of endometriosis may include pelvic, back or flank pain before and during menstruation, very painful menstrual cramps, abnormal or heavy menstrual flow and bowel and urinary symptoms. The purpose of endometriosis treatment is to control the hormonal stimulation of the endometrial tissue to reduce or stop bleeding each month.23 COCs may serve this purpose, but further research is needed. A Cochrane review found that there was little evidence available regarding use of cyclic 4 9:35 AM Page 4 COCs for the treatment of endometriosis pain despite their frequent use.24 If pain is linked to hormone withdrawal, maintaining hormone levels with continuous use of a COC has the potential to prevent endometriosis pain and promote endometrial atrophy and amenorrhea.23 A continuous low-dose COC was compared to daily cyproterone acetate 12.5 mg in one endometriosis study.25 Patients had undergone surgery for endometriosis and were experiencing recurrent pain. After 3 months of therapy, 46% of 41 women taking the COC were amenorrheic compared to 65% of 43 women taking cyproterone acetate. The researchers concluded that both treatments were similarly effective in reducing pelvic pain after surgery and were generally well tolerated. Both improved health-related quality of life as well. Polycystic ovary syndrome The main endocrine abnormalities seen in women with polycystic ovary syndrome (PCOS) are elevated LH levels and insulin resistance.26 High LH and hyperinsulinemia contribute to ovarian growth and cyst formation and increased production of androgens.26 Women are at higher risk of cardiovascular disease. Ovulation does not occur regularly and this contributes to irregular menstrual cycles. Excessive estrogen production without postovulatory progesterone can contribute to endometrial proliferation and increased risk of endometrial cancer. For women who desire contraception, combined hormonal contraceptives are a treatment of choice for PCOS.27 The progestin component in the COC provides endometrial protection from unopposed estrogen and reduces risk of endometrial cancer. COCs also reduce androgen levels by suppressing FSH and LH, which decrease ovarian androgen production, and by increasing levels of sex hormone binding globulin, which binds to testosterone. Large randomized, controlled trials comparing continuous and cyclic COCs have not been done. In a small study, 14 women with PCOS took a cyclic COC, continuous COC or a gonadotropin releasing hormone agonist (leuprolide acetate) for 3 months.28 In the women | Continuous Use of Combined Oral Contraceptives on cyclic COC, LH and testosterone levels increased during the 7-day pill-free interval. LH and testosterone levels remained suppressed in the women on continuous COC. A cohort study of continuous ethinyl estradiol and cyproterone acetate for 36 cycles in 66 women with PCOS concluded that for symptoms due to androgen excess including acne, hirsutism and seborrhea, continuous administration of a hormonal contraceptive may be necessary to maintain symptom control.29 ADVERSE EFFECTS OF CONTINUOUS COMBINED ORAL CONTRACEPTIVES Breakthrough uterine bleeding and spotting are possible side effects with any hormonal contraceptive product and are one of the most frequent reasons for discontinuation.30 Generally, breakthrough bleeding is heavier and may require sanitary protection while spotting is very light bleeding that may not require protection. Factors that may contribute to breakthrough bleeding include irregular pill taking, smoking, pill malabsorption, pregnancy, uterine or cervical pathology and drug interactions (see Table 2).11 Irregular or unpredictable breakthrough bleeding or spotting may occur with a continuous COC. One review concluded that breakthrough bleeding or spotting may be more common in new COC users compared to women who switch from a cyclic COC regimen to a continuous regimen.31 Two studies compared bleeding patterns of continuous and cyclic COCs containing 20 µg ethinyl estradiol and 100 µg levonorgestrel.32,33 Both found that women on continuous COC reported significantly fewer bleeding days requiring sanitary protection and were more likely to be amenorrheic (no bleeding or spotting) than women on cyclic COC. In one study,32 women kept a daily bleeding calendar for 6 cycles or 168 days.32 By cycle 5, 9 out of 16 women in the continuous group reported amenorrhea compared to 1 out of 16 in the cyclic group. In the other study, 60 out of 79 women randomized completed 12 cycles or 336 days of COC.33 During cycles 1 to 3, 16% of women in the continuous group reported amenorrhea compared to Answer online at www.pharmacygateway.ca | May 2006 WYETH_CE_Contraceptive_0506_E 4/27/06 0% in the cyclic group. During cycles 10-12, 72% of women in the continuous group reported amenorrhea compared to 4% in the cyclic group. In the phase 3 study of continuous ethinyl estradiol 20 µg/levonorgestrel 90 µg, 44.8% of women had no spotting or bleeding after seven 28-day cycles of pill use;6 70.8% of participants experienced either spotting only or no bleeding after this length of time. Other side effects of COCs are generally mild and occur most often during the first three months of use. Nausea, weight changes, mood changes, bloating, breast tenderness and headaches may occur.11 In one prospective study, 27% of women discontinued taking COCs because of side effects.30 In studies comparing continuous with standard COC, women reported similar incidences of headache, breast tenderness, nausea, depression and PMS. Continuous participants reported less bloating and menstrual pain however.32,33 LONG-TERM SAFETY OF CONTINUOUS COMBINED ORAL CONTRACEPTIVES Reproductive cancers Current evidence regarding how COCs affect risk of hormone sensitive cancers such as endometrial, ovarian and breast cancer does not distinguish between cyclic or continuous use. The information available reflects current history of COC use, which has primarily been cyclic. Further study is warranted to confirm the effects of long-term continuous COC use on cancer risk. Some researchers feel that the incessant ovulation that occurs from menarche to menopause in women is to blame for the increasing incidence of reproductive cancers in women who live in developed countries.34 There is good evidence that by suppressing ovulation, COCs reduce the risk of ovarian cancer. A recent review estimates that rates of ovarian cancer are 40-50% lower in women who have ever used combined hormonal contraceptives and this protective effect appears to increase with longer duration of COC use.35 Endometrial cancer risk is estimated to be reduced by 90% with COC use.35 Ultrasound and endometrial biopsy 9:35 AM Page 5 results from patients in continuous COC studies provide reassurance that the endometrial lining does not build up with continuous COC use.33,36 Although these studies were only one year long, no hyperplasia was observed within this time. The concern is that endometrial hyperplasia may progress to cancer. A small increase in breast cancer risk (RR 1.24) occurs among women under the age of 35 when they are taking COCs and for a period of 10 years after discontinuing COCs.37 Because this is a time when breast cancer incidence is lowest, absolute risk is small. However, even a small increased risk is significant because of the large numbers of young women who take COCs. In women aged 35 to 64 years, current or past use of COCs is not associated with a significant increased risk of breast cancer.37 Ethinyl estradiol doses above 35 µg may confer greater risk of breast cancer.38 It is possible that cumulative dose of estrogen and progestin has greater impact on breast cancer risk than the manner by which it is taken. Risk of blood clots A small, elevated risk of venous thromboembolism occurs with low-dose COC use. Risk is increased by 3- to 6-fold compared to nonusers.39 This risk is highest in the first year of use and increases with other genetic (family history) or acquired (obesity) risk factors for thrombosis.39 Absolute risk is estimated to be 1 to 1.5 events per 10,000 users per year of use.11 Currently there is no information regarding whether a continuous COC regimen will affect risk of blood clots differently than a standard COC regimen. Return of fertility It appears that fertility may return relatively quickly following continuous use of a COC. A recent study evaluated ovarian suppression and return to ovulation following 84 days of continuous ethinyl estradiol 20 µg/levonorgestrel 90 µg.40 Of 37 women who participated in the study, all had documented ovulation prior to the study. During an 84-day treatment period, none of the women ovulated and all resumed ovulation within 31 days of stopping the COC. In another continuous COC study, one May 2006 | Answer online at www.pharmacygateway.ca woman became pregnant immediately after discontinuing continuous COC administration.33 It was previously confirmed by transvaginal ultrasound at study completion that her endometrium was inactive. ACCEPTANCE OF CONTINUOUS COMBINED ORAL CONTRACEPTIVES Old habits are hard to break. It may seem strange or unnatural for women to be able to manipulate their menstrual cycles. However, once educated about the potential benefits of a long-cycle or continuous COC regimen, most women are willing to give it a try. Many find it acceptable and refuse to go back to a standard regimen. Surveys of women have indicated that up to 70% of women would prefer not to have a period every month.4,41 Fifty percent of women over the age of 45 would choose not to menstruate at all.41 One survey also sampled providers and found that 44% agreed that menstrual suppression is a good idea.4 In a retrospective review, patients who were taking a standard 21/7 COC regimen were given the option of extending their active tablets for 6, 9 or 12 weeks or indefinitely because of hormone withdrawal symptoms such as headaches, dysmenorrhea, hypermenorrhea and PMS, convenience, endometriosis and menstrual-associated acne.42 0f 292 patients followed, 91% of patients tried an extended regimen. Of these, 57 chose to stop using COCs due to a worsening of side effects or a reduced need for contraception. Thirty-eight patients chose to return to the standard 21/7 regimen because of side effects including increased breakthrough bleeding or spotting or other concerns. The majority of women, 59% of 292 women, continued with an extended regimen. These patients reported an improvement in their original problem and their quality of life. Another potential benefit of continuous COCs is cost savings. Once women on a continuous regimen are amenorrheic, sanitary products are no longer required. It is also likely that women with severe cycle-related complaints will miss fewer workdays when symptoms are better controlled. Continuous Use of Combined Oral Contraceptives | 5 WYETH_CE_Contraceptive_0506_E 4/27/06 THE PHARMACIST’S ROLE Pharmacists, as the most accessible health professionals, are in a position to educate women about birth control options available to them. A continuous COC may not be best for all women, but many will find it an attractive option. Pharmacists can screen for women who might benefit from a continuous regimen. They can ask their patients on standard COC regimens whether or not they experience bothersome hormone withdrawal symptoms such as headaches, menstrual cramps, breast tenderness or bloating. Patients taking medication for dysmenorrhea, endometriosis or menstrual migraines may also be candidates. Pharmacists have an essential role to play in counselling patients about the proper use of COCs prescribed continuously. Patients may use any of the currently available monophasic combined hormonal contraceptives continuously, without the usual hormone-free interval between packages. When a continuoususe COC becomes available in Canada, this may be a convenient option for women. Taking the COC without interruption between packages is important and pharmacists should reinforce this. This helps to ensure contraceptive efficacy and minimizes hormone fluctuations that can contribute to side effects. Pharmacists may recommend that their patients keep an extra package of COC on hand instead of waiting until a package is finished to obtain their next refill. Pharmacists must be knowledgeable about common side effects of continuous COCs and how they can be managed. Most women who discontinue COCs do so within the first two months of use.30 Taking the pill at bedtime or with a small meal or snack may help to relieve nausea. Sometimes, dietary changes such as reducing caffeine and salt may help with bloating and breast tenderness. The most important thing for women starting or switching to continuous COCs to know is that breakthrough bleeding or spotting is possible and may be irregular and unpredictable. Patients should be reassured that breakthrough bleeding or spotting is not harmful, does not indicate a lack of contraceptive efficacy and will usually 6 9:35 AM Page 6 resolve on its own. The majority of women do not have any bleeding after 12 months on a continuous regimen. Women should be counselled to take their pill at the same time each day to minimize fluctuations in hormone levels that may contribute to adverse effects. Pharmacists should also be familiar with absolute and relative contraindications to COCs and about potential drug interactions that may occur between COCs and current or new medications. (See Tables 2, 3 and 4.) TABLE 2: SUMMARY • <6 weeks postpartum if breastfeeding • smoker over the age of 35 (≥15 cigarettes/day) • hypertension (≥160/100 mmHg) • current or past history of venous thromboembolism (VTE) • ischemic heart disease • history of cerebrovascular accident • complicated valvular heart disease • migraine headache with aura • current breast cancer • diabetes with complications • severe cirrhosis • liver tumour Taking combined oral contraceptives on a continuous basis may seem unnatural to many who feel that monthly menstruation is normal and necessary for women. However, there may be advantages to a continuous regimen. Many women who take COCs cyclically may experience bothersome symptoms associated with withdrawal bleeding each month. Extending active COC tablets may eliminate some or all of these symptoms. For women with hormone sensitive conditions such as PMS, menstrual migraines, endometriosis or PCOS, maintaining constant hormone levels with a continuous COC may contribute to symptom improvement. However, more well-designed trials are needed to provide additional supportive evidence for these uses. For pregnancy prevention, evidence indicates that continuous COCs are as effective as cyclic COCs. Although women on continuous COC regimens may experience more irregular or unpredictable bleeding, for most this will lessen as time goes on. REFERENCES 1. Wilkins K, Johansen H, Beaudet M, et al. Oral Contraceptive Use. Statistics Canada. Health Reports 2000;11(4):25-37. 2. Gladwell M. John Rock’s Error. The New Yorker 2000;(March 13):52-63. 3. Kaunitz, Andrew M. Menstruation: Choosing whether… and when. Contraception 2000;62:277-84. 4. Andrist L, Arias R, Nucotola D, et al. Women’s and providers’ attitudes toward menstrual suppression with extended use of oral contraceptives. Contraception 2004;70:359-63. 5. Wiegratz I, Kuhl H. Long-cycle treatment with oral contraceptives. Drugs 2004;64(21):2447-62. 6. Archer D, Jensen J, Johnson H, et al. Efficacy and safety of a continuous-use regimen of levonorgestrel/ethinyl estradiol: North American phase 3 study results. Abstract. 2005 Conjoint Meeting of the American Society for Reproductive Medicine and the | Continuous Use of Combined Oral Contraceptives Drug interactions11 Medications that may contribute to combined oral contraceptive failure anti-epileptics: carbamazepine, phenobarbital, phenytoin, primidone, topiramate antimicrobials: griseofulvin, rifampin ritonavir OTC: St. John’s Wort TABLE 3: TABLE 4: Absolute contraindications to combined oral contraceptives11 Relative contraindications to combined oral contraceptives11 • smoker over the age of 35 (<15 cigarettes/day) • adequately controlled hypertension • hypertension (140-59/90-99 mmHg) • migraine headache over the age of 35 • symptomatic gallbladder disease • mild cirrhosis • history of combined OC-related cholestasis • taking medications that may interfere with combined OC metabolism Canadian Fertility and Andrology Society. 7. Sulak P, Carl J, Gopalakrishnan I, et al. Outcomes of extended oral contraceptive regimens with a shortened hormone-free interval to manage breakthrough bleeding. Contraception 2004;70(4):281-7. 8. Sulak P, Scow R, Preece C, et al. Hormone withdrawal symptoms in oral contraceptive users. Obstet Gynecol 2000;95:261-6. 9. Sulak P, Cressman B, Waldrop E, et al. Extending the duration of active oral contraceptive pills to manage hormone withdrawal symptoms. Obstetrics & Gynecology Feb 1997;89(2):179-83. 10. Freeman E, Borisute H, Deal L, et al. A continuous-use regimen of levonorgestrel/ethinyl estradiol significantly alleviates cycle-related symptoms: results of a phase 3 study. Abstract. 2005 Conjoint Meeting of the American Society for Reproductive Medicine and the Canadian Fertility and Andrology Society. 11. Black A, Francoeur D, Rowe T. SOGC Clinical Answer online at www.pharmacygateway.ca | May 2006 WYETH_CE_Contraceptive_0506_E 4/27/06 9:35 AM Practice Guidelines Canadian Contraception Consensus Part 2. J Obstet Gynecol Can 2004 Mar;143:219-54. 12. Black A, Francoeur D, Rowe T. SOGC Clinical Practice Guidelines Canadian Contraception Consensus Part 1. J Obstet Gynecol Can 2004 Feb;143:143-56. 13. Killick SR. Ovarian follicles during oral contraceptive cycles: Their potential for ovulation. Fertility & Sterility 1989 Oct;52(40):580-2. 14. Spona J, Elstein M, Feichtinger W, et al. Shorter pill-free interval in combined oral contraceptives decreases follicular development. Contraception 1996 Aug;54(2):71-7. 15. Schlaff W, Lynch A, Hughes H, et al. Manipulation of the pill-free interval in oral contraceptive pill users: The effect on follicular suppression. Am J Obstet Gynecol 2004;190:943-51. 16. Edelman A, Gallo M, Jensen J, et al. Continuous or extended cycle vs. cyclic use of combined oral contraceptives for contraception. The Cochrane Database of Systematic Reviews. The Cochrane Collaboration. 2006, Volume 1. 17. Kessel B. Premenstrual syndrome. Advances in diagnosis and treatment. Obstetrics & Gynecology Clinics of North America Sep 2000;27(3):625-39. 18. Backstrom T. Oral contraceptives in premenstrual syndrome: A randomized comparison of triphasic and monophasic preparations. Contraception Sep 1992;46(3):253-68. 19. Freeman E. Evaluation of a unique oral contraceptive (Yasmin) in the management of premenstrual dysphoric disorder. European Journal of Contraception & Reproductive Health Care Dec 2002;7 Suppl 3:27-34, 42-3. 20. Hutchinson, S. Hormonal influence on migraine. Clinics in Family Practice Sep 2005;7(3): 529-43. 21. Chavanu K, O’Donnell D. Hormonal interventions for menstrual migraines. Pharmacotherapy Nov 2002;22(11):1442-57. 22. Becker W. Use of oral contraceptives in patients with migraine. Neurology Sep 1999;53(4) Page 7 Suppl.1:S19-25. 23. Winkel C. Evaluation and management of women with endometriosis. Obstetrics & Gynecology Aug 2003;102(2):397-408. 24. Moore J, Kennedy S, Prentice A. Modern combined oral contraceptives for pain associated with endometriosis. The Cochrane Database of Systematic Reviews. The Cochrane Collaboration. 2005, Volume 4. 25. Vercellini P, De Giorgi O, Mosconi P, et al. Cyproterone acetate versus a continuous monophasic oral contraceptive in the treatment of recurrent pelvic pain after conservative surgery for symptomatic endometriosis. Fertility & Sterility Jan 2002;77(1):52-61. 26. Pannill M. Polycystic ovary syndrome: An overview. Topics in Advanced Practice Nursing eJournal 2002;2(3). 27. Richardson M. Current perspectives in polycystic ovary syndrome. American Family Physician Aug 2003;68(4):697-704. 28. Ruchhoft E, Elkind-Hirsch K, Malinak R. Pituitary function is altered during the same cycle in women with polycystic ovary syndrome treated with continuous or cyclic oral contraceptives or a gonadotropin-releasing hormone agonist. Fertility & Sterility Jul 1996;66(1):54-60. 29. Falsetti L, Galbignani E. Long-term treatment with the combination ethinylestradiol and cyproterone acetate in polycystic ovary syndrome. Contraception Dec 1990;42(6):611-9. 30. Rosenberg M, Waugh M. Oral contraceptive discontinuation: A prospective evaluation of frequency and reasons. American Journal of Obstetrics & Gynecology Sep 1998;179(3):577-82. 31. Henzl M, Polan M. Avoiding menstruation—A review of health and lifestyle issues. J Reprod Med Mar 2004;49(3):162-74. 32. Kwiecien M, Edelman A, Nichols M, et al. Bleeding patterns and patient acceptability of standard or continuous dosing regimens of a low-dose oral contraceptive: A randomized trial. Contraception 2003;67:9-13. 33. Miller L, Hughes J. Continuous combination oral contraceptive pills to eliminate withdrawal bleeding: A randomized trial. Obstetrics & Gynecology Apr 2003;101(4):653-61. 34. Eaton SB, Pike M, Short R, et al. Women’s reproductive cancers in evolutionary context. The Quarterly Review of Biology Sep 1994;69(3):353-67. 35. Rager K, Omar H. Hormonal contraception: Noncontraceptive benefits and medical contraindications. Adolesc Med 2005;16:539-51. 36. Johnson J, Grubb G. Endometrial histology in subjects on a continuous-use regimen of levonorgestrel/ethinyl estradiol: Results of a phase 3 study. Abstract. 37. Collins J, Crosignani P for the ESHRE Capri Workshop Group. Hormones and breast cancer. Human Reproduction Update 2004;10(4):281-93. 38. Althuis M, Brogan D, Coates R, et al. Hormonal content and potency of oral contraceptives and breast cancer risk among young women. British Journal of Cancer Jan 2003;88(1):50-7. 39. Tanis B, Rosendaal F. Venous and arterial thrombosis during oral contraceptive use: Risks and risk factors. Seminars in Vascular Medicine Feb 2003;3(1):69-84. 40. Archer D, Kovalevsky G, Ballagh S, et al. Effect on ovarian activity of a continuous-use regimen of oral levonorgestrel/ethinyl estradiol. Abstract. 2005 Conjoint Meeting of the American Society for Reproductive Medicine and the Canadian Fertility and Andrology Society. 41. den Tonkelaar I, Oddens B. Preferred frequency and characteristics of menstrual bleeding in relation to reproductive status, oral contraceptive use, and hormone replacement therapy use. Contraception Jun 1999;59(6):357-62. 42. Sulak P, Kuehl T, Ortiz M, Shull B. Acceptance of altering the standard 21-day/7-day oral contraceptive regimen to delay menses and reduce hormone withdrawal symptoms. Am J Obstet Gynecol Jun 2002;186(6):1142-9. QUESTIONS 1. Common COC withdrawal symptoms include all of the following EXCEPT: a) headaches b) abdominal bloating c) breast tenderness d) leg cramps 2. Continuous COCs might be a good option for all of the following patients EXCEPT: a) an active-duty female military recruit b) a new mom who is breastfeeding c) an athlete training for a triathlon d) a 16-year-old girl with heavy periods every 2 to 3 months 3. What percentage of women will have no bleeding after 6 months of continuous combined hormonal contraception? a) 70% b) 100% c) 40% d) 50% 4. Which statement best describes uterine bleeding that can occur with a continuous COC regimen? a) regular withdrawal bleeding every 28 days b) regular withdrawal bleeding every 91 days c) irregular bleeding or spotting that gradually lessens over several months d) regular monthly bleeding with irregular spotting in between 5. Regarding contraceptive efficacy, which statement(s) is/are TRUE? a) The Pearl Index is the value used to describe the number of pregnancies expected to occur in 100 women using a contraceptive method for one year. b) Current evidence indicates that continuous COCs are clearly more effective than standard 21/7 COCs. c) Current evidence indicates that continuous COCs are clearly less effec- May 2006 | Answer online at www.pharmacygateway.ca tive than standard 21/7 COCs. d) a and b e) a and c 6. All of the following factors can increase the likelihood of ovulation occurring with a continuous COC EXCEPT: a) fluctuation of FSH and LH levels b) missing several pills in a row because of having the stomach flu c) taking topiramate for migraine prophylaxis d) inconsistent pill-taking times 7. JR is a 25-year-old woman with a very busy job and active lifestyle. She has a history of horrible monthly periods with severe bloating, cramping and heavy flow. She is getting married in two months and would like some information about “the pill”. What is the BEST information to give her? Continuous Use of Combined Oral Contraceptives | 7 WYETH_CE_Contraceptive_0506_E 4/27/06 9:35 AM Page 8 QUESTIONS continued a) There are many combined hormonal contraceptives available including a pill, transdermal patch and vaginal ring. b) She could try naproxen sodium for her menstrual cramps and use condoms. A COC will most likely worsen her period-related symptoms. c) A continuous COC might help relieve her hormone withdrawal symptoms and will provide effective birth control. d) All of the above. 8. JR’s physician prescribes a COC to be taken on a continuous basis. Which side effect is most likely? a) nausea with or without vomiting b) migraine headaches c) weight gain of 5 pounds d) chloasma—a darkening of facial skin pigmentation 9. You may want to discuss some of the non-contraceptive benefits of COCs with JR. They include the following EXCEPT: a) decreased risk of cervical cancer b) decreased risk of endometrial cancer c) decreased risk of ovarian cancer d) improved acne and hirsutism 10. Appropriate information to tell JR about the breakthrough bleeding or spotting that can occur with a continuous COC includes which of the following? a) If this occurs she should notify her physician immediately. b) This is common and will taper off over time. c) Missing pills may contribute to bleeding or spotting. d) b and c e) all of the above 11. A continuous COC may help symptoms associated with severe PMS by the following mechanism: a) prevention of estrogen and progesterone fluctuations which can exacerbate symptoms b) binding to testosterone which can contribute to acne c) prevention of FSH surges which contribute to mood swings d) all of the above 12. All of the following conditions can be aggravated by hormonal fluctuations EXCEPT: 8 | Continuous Use of Combined Oral Contraceptives a) b) c) d) menstrual migraines cluster headaches endometriosis polycystic ovary syndrome 13. CS is a 34-year-old woman who has suffered from migraine headaches since puberty. She takes rizatriptan and flurbiprofen to help manage her migraine symptoms. She is currently not taking any other medications. Over the last few months her migraines have increased in frequency. What would be your first suggestion for CS? a) She should change her migraine medications. b) She should keep a detailed migraine diary to determine possible migraine triggers and the timing of attacks relative to her menstrual cycle. c) She should start continuous hormonal contraception. d) She should take daily low-dose ASA to reduce her risk of stroke. 14. After keeping a migraine diary for 3 months, CS realizes that most of her migraines occur within a few days of her period starting. She is diagnosed with menstrual migraine and her physician starts her on a continuous course of a low-dose OC. What should she monitor? a) frequency and severity of migraines b) presence and amount of breakthrough bleeding or spotting c) presence and nature of an aura that occurs with her migraines d) a and c e) all of the above 15. TG is a 30-year-old woman with endometriosis. Which statement(s) about endometriosis is/are TRUE? a) endometrial tissue grows outside of the uterus and bleeds each month in response to normal hormone fluctuations b) symptoms include severe dysmenorrhea, heavy flow and constipation c) treatment is aimed at reducing hormonal stimulation of endometrial tissue d) a and c e) all of the above 16. TG’s physician prescribes a continuous low-dose COC for her. The desired primary outcome of this therapy is: a) TG will become amenorrheic and will no longer have dysmenorrhea and menorrhagia b) TG will not get pregnant c) TG’s androgen levels will be suppressed. d) TG will not develop menstrual migraines. 17. Continuous COCs may help control symptoms related to androgen excess with polycystic ovary syndrome by the following mechanism: a) lowering endogenous estrogen and progesterone levels b) causing weight loss which reduces insulin resistance c) increasing sex hormone binding globulin which binds to testosterone d) increasing production of testosterone in the ovaries 18. Which statement is TRUE? a) It takes 6 months for fertility to return following a course of continuous combined oral contraception. b) Most physicians would not be willing to prescribe an extended or continuous COC regimen. c) Having a menstrual period every month is medically necessary except during pregnancy. d) The majority of women would prefer not to have a period every month. 19. All of the following have the potential to interact with COCs and may reduce their effectiveness except: a) gingko biloba b) carbamazepine c) St. John’s Wort d) rifampin 20. ML is a 28-year-old married woman who has been taking a COC on a continuous basis for the past three years. She prefers not to menstruate and tolerates this regimen well. However, she and her husband would like to have a baby. Although return of ovulation does not guarantee pregnancy, how soon might ovulation return following discontinuation of the COC? a) two months b) one year c) three months d) one month Answer online at www.pharmacygateway.ca | May 2006 To answer this CE lesson online If currently logged into our Online Ce Program, please return to the “Lessons Available Online” Page and click on “Link to questions” for this CE Lesson. 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