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6 VOLUME 38 : NUMBER 1 : FEBRUARY 2015 ARTICLE Full text free online at www.australianprescriber.com Mary Stewart Senior medical officer Research and Education Family Planning NSW Kirsten Black Associate professor Discipline of Obstetrics, Gynaecology and Neonatology University of Sydney Key words combined oral contraceptives, oestrogens, progestogens, venous thromboembolism Aust Prescr 2015;38:6–11 Choosing a combined oral contraceptive pill SUMMARY The combined oral contraceptive pill is an effective contraceptive method which can also offer other benefits. However, other contraceptive options should be discussed. If the pill is the chosen method, prescribe a pill with the lowest effective dose of oestrogen and progestogen. Pills containing levonorgestrel or norethisterone in combination with ethinyloestradiol 35 microgram or less are considered first-line. They are effective if taken correctly, have a relatively low risk of venous thromboembolism, and are listed on the Pharmaceutical Benefits Scheme. The pill is usually taken in a monthly cycle. Some women may prefer an extended pill regimen with fewer or no inactive pills. Oestrogens Ethinyloestradiol, a derivative of 17 beta-oestradiol, has been the predominant oestrogen in contraceptive pills because of its high oral bioavailability. Until recently oestradiol had not been used due to its rapid inactivation by the liver, short half-life and the occurrence of breakthrough bleeding when combined with older progestogens. However, formulations that combine oestradiol (1.5 mg) in a micronised form with a newer progestogen (nomegestrol) appear to offer good cycle control.8 Oestradiol has also been combined with a synthetic ester in the form of oestradiol valerate to improve its oral bioavailability and extend its half-life.9 At the doses prescribed in pills, oestradiol may have a more favourable impact on haemostasis and lipid and carbohydrate metabolism (and therefore on cardiovascular risk) when compared with ethinyloestradiol.10,11 However, there is insufficient evidence to preferentially prescribe these pills to women with cardiovascular risk factors.12 Progestogens Pills containing levonorgestrel or norethisterone have been used since the 1960s. The combination of these progestogens with 35 microgram or less of ethinyloestradiol is considered the ‘gold standard’ in relation to their safety profile. As most of these combinations are listed on the Pharmaceutical Benefits Scheme (PBS) they are an effective first-line option for women preferring an oral contraceptive. Newer progestogens such as gestodene and desogestrel are structurally related to progesterone, but have greater specificity for progesterone receptors than the older progestogens. They reduce the potential for androgenic, oestrogenic and glucocorticoid effects. Drospirenone is a Introduction The combined oral contraceptive pill contains oestrogen and progestogen. It was introduced into Australia just over 50 years ago. Australia was the second country in the world to have access to ‘the pill’. Women rapidly adopted the pill as it allowed the reliable separation of sex and reproduction and gave them the opportunity to plan when to have children. Since then the pill has been further developed to ensure good efficacy while minimising the adverse effects. A key advance was a decrease in the dose of oestrogen to the currently used low-dose formulation (standard dose of ≤35 microgram ethinyloestradiol).1 Subsequently it has been found that formulations with ethinyloestradiol 20 microgram are likely to be as effective as the 30–35 microgram pills while possibly reducing the oestrogenic effects such as nausea, bloating and breast tenderness.2 However, there may be an increase in unscheduled bleeding.3 More recent developments, which may improve the safety and efficacy of the combined oral contraceptive pill, include using oestradiol instead of ethinyloestradiol and extended pill regimens with fewer or no inactive pills.4-6 The pill today The pill is the most commonly used contraceptive method and approximately 50–80% of Australian women use it at some stage during their reproductive lives.7 There is now a large range of products available with over 30 different registered brands. While many of these pills contain similar hormones and doses, there are multiple formulations for the prescriber to consider (Table 1). These pills contain an oestrogen component (ethinyloestradiol, mestranol, oestradiol or its pro-drug oestradiol valerate) and a progestogen (levonorgestrel, norethisterone, gestodene, desogestrel, drospirenone, nomegestrol, dienogest or cyproterone). This article has a continuing professional development activity for pharmacists available at www.australianprescriber.com/ continuing-professional- development 7 ARTICLE Full text free online at www.australianprescriber.com VOLUME 38 : NUMBER 1 : FEBRUARY 2015 Table 1 Combined oral contraceptive pills Brand name Oestrogen Progestogen PBS listing Femme-Tab ED 20/100 Microgynon 20 ED Microlevlen ED Loette Micronelle 20 ED 20 microgram ethinyloestradiol 100 microgram levonorgestrel Only Femme-Tab ED 20/100 PBS listed Femme-Tab ED 30/150 Levlen ED Microgynon 30 ED Monofeme Nordette Evelyn 150/30 ED Eleanor 150/30 ED Micronelle 30 ED 30 microgram ethinyloestradiol 150 microgram levonorgestrel PBS listed Microgynon 50 ED 50 microgram ethinyloestradiol 125 microgram levonorgestrel Logynon ED Trifeme 28 Triphasil Triquilar ED 6 x 30 microgram ethinyloestradiol 6 x 50 microgram levonorgestrel 5 x 40 microgram ethinyloestradiol 5 x 75 microgram levonorgestrel 10 x 30 microgram ethinyloestradiol 10 x 125 microgram levonorgestrel Brevinor 21 and 28 Day Norimin 28 Day 35 microgram ethinyloestradiol 500 microgram norethisterone PBS listed Brevinor-1 21 and 28 Day Norimin-1 28 Day 35 microgram ethinyloestradiol 1000 microgram norethisterone Norinyl-1 21 and 28 Day 50 microgram mestranol 1000 microgram norethisterone Improvil 28 Day Synphasic 28 7 x 35 microgram ethinyloestradiol 500 microgram norethisterone 9 x 35 microgram ethinyloestradiol 1000 microgram norethisterone 5 x 35 microgram ethinyloestradiol 500 microgram norethisterone Marvelon 28 Madeline 30 microgram ethinyloestradiol 150 microgram desogestrel Not PBS listed Minulet 30 microgram ethinyloestradiol 75 microgram gestodene Brenda-35 ED Carolyn-35 ED Diane-35 ED Estelle-35 ED Jene-35 ED Juliet-35 ED Laila-35 ED 35 microgram ethinyloestradiol 2 mg cyproterone acetate Yaz Yaz Flex 20 microgram ethinyloestradiol 3 mg drospirenone Isabelle Petibelle Yasmin 30 microgram ethinyloestradiol 3 mg drospirenone Valette 30 microgram ethinyloestradiol 2 mg dienogest Qlaira 2 x 3 mg oestradiol valerate – 5 x 2 mg oestradiol valerate 5 x 2 mg dienogest 17 x 2 mg oestradiol valerate 17 x 3 mg dienogest 2 x 1 mg oestradiol valerate – Zoely 1.5 mg oestradiol 2.5 mg nomegestrol acetate PBS Pharmaceutical Benefits Scheme 8 ARTICLE Full text free online at www.australianprescriber.com VOLUME 38 : NUMBER 1 : FEBRUARY 2015 Choosing a combined oral contraceptive pill profile or cycle control. A quadriphasic combined oral contraceptive pill that contains oestradiol valerate and desogestrel is formulated with an oestrogen step- down and progestogen step-up sequence.15 The pill is a user-dependent method. Its failure rate therefore differs between ‘perfect use’ (0.3% annually) by women who take it consistently and correctly and ‘typical use’ (9% annually) when the pill is used inconsistently or incorrectly.16 Safety and tolerability Long-term cohort studies show that, compared to non-users of the combined oral contraceptive pill, users have lower rates of death from any cause. They also have significantly lower rates of death from cancer, cardiovascular disease and other diseases.17 Women may experience a range of adverse effects and managing these can be challenging. Table 2 outlines some common adverse effects and strategies that may improve the symptoms should the woman wish to continue with the pill. Although trying another oral formulation can be helpful, sometimes a change to another form of contraception may be appropriate. This includes a progestogen-only method, such as the contraceptive implant or levonorgestrel intrauterine system, or the non-hormonal copper intrauterine device. These long-acting reversible contraceptive methods are much more effective at preventing unintended pregnancy compared to the pill. They should be discussed with all women requesting contraception, particularly those who cannot take the pill because of adverse effects or identified risk factors or who find it difficult to remember to take the pill daily. The combined oral contraceptive pill is not recommended during lactation as it may affect breast milk volume. Venous thromboembolism There is a risk of venous thromboembolism associated with the combined hormonal contraception, but the risk is much less than that during pregnancy and the immediate postpartum period. Non-users of hormonal contraception have a baseline risk for venous thromboembolism of around 20 per 100 000 woman-years. Current research points to a three-fold increased risk of venous thromboembolism for women using a combined pill over baseline (Table 3).19,20 Women should be informed of the risk of venous thromboembolism with combined oral contraceptive pills and be aware of the signs. The factors that influence the risk include age, smoking, body mass index, immobilisation, and a personal or family history of thromboembolism or thrombogenic mutations. These factors need to be assessed when considering spironolactone analogue and has a mild diuretic effect. Cyproterone has anti-androgenic effects which may be beneficial in women with severe acne. Guiding pill prescription The guiding principles when considering which pill to prescribe for an individual woman are to choose a formulation that: • has the lowest dose of oestrogen and progestogen to provide good cycle control and effective contraception • is well tolerated • has the best safety profile • is affordable • offers additional non-contraceptive benefits if desired. Effective regimens The first available formulation of the combined oral contraceptive pill contained 50 microgram of ethinyloestradiol for cycle control. However, an association between the pill and venous thromboembolism soon emerged. This was due to the effect of oestrogen on the synthesis of clotting factors.13 To mitigate this risk, and reduce oestrogenic adverse effects, the dose of ethinyloestradiol was reduced to 35 and 30 microgram and more recently 20 microgram without an apparent loss of contraceptive efficacy.3 The pills available in Australia are mostly in 28-day packs with 21 active and 7 inactive pills, to mimic the menstrual cycle. Some formulations contain 24 active and 4 inactive pills (24/4 regimes) which may reduce the chance of contraceptive failure and breakthrough ovulation.4 Extended pill-taking regimens are used by many women to delay or avoid a withdrawal bleed. This is most easily achieved with monophasic regimens in which each active pill contains the same amount of oestrogen and progestogen and the inactive pills are skipped. Typically this is done for three months at a time. Indeed evidence is available to support the safety of continuous use of the contraceptive pill for up to 12 months.14 Another approach is called a ‘menstrually signalled’ regimen. Women take the pill continuously until they experience four days of vaginal spotting or bleeding after which they have a four-day pill break. Triphasic pills are commonly prescribed in Australia, but have no evidence-based advantage over monophasic pills in relation to their adverse effect Women with significant risk factors for venous thromboembolism are not suitable for any combined hormonal method 9 ARTICLE Full text free online at www.australianprescriber.com VOLUME 38 : NUMBER 1 : FEBRUARY 2015 Arterial disease Combined oral contraceptive pills are associated with an increase in the risk of myocardial infarction and ischaemic stroke. While the odds ratio for these events is around 1.7 (compared to non-users), the absolute risk is very low and depending on age lies between 2 and 20 per million women.24-26 Women with significant risk factors for arterial disease such as a personal history of arterial disease, obesity, smoking (if over 35 years old), migraine with aura, diabetes with vascular complications or uncontrolled hypertension should not use any combined hormonal method.27 the safety of the combined oral contraceptive pill. If a woman has a significant risk factor for venous thromboembolism, she is not suitable for any combined hormonal method. Progestogen-only methods are safer for women with risk factors for venous thromboembolism. The risk of venous thromboembolism appears to vary with oestrogen dose and progestogen type. Pills containing 50 microgram ethinyloestradiol have the highest risk. Compared with pills containing levonorgestrel, those with desogestrel, gestodene, cyproterone acetate and drospirenone may have a higher risk, although the evidence is conflicting.21-23 Table 2 Managing common adverse effects associated with the combined oral contraceptive pill Problem Management strategies based on practice Nausea Reduce oestrogen dose Exclude pregnancy Take pills at night Change to progestogen-only method Breast tenderness Reduce oestrogen and/or progestogen dose Change progestogen Consider using a pill containing drospirenone Bloating and fluid retention Reduce oestrogen dose Change to progestogen with mild diuretic effect (i.e. drospirenone) Headache Reduce oestrogen dose and/or change progestogen If headache occurs in hormone-free week, consider: • extended use or • giving oestradiol 50 microgram transdermal patch in this week or • try oestradiol valerate/dienogest pill18 Dysmenorrhoea Extended pill regimen to reduce the frequency of bleeding Decreased libido No evidence supports a benefit of one type of oral contraceptive pill over another Breakthrough bleeding If taking an ethinyloestradiol 20 microgram pill, increase oestrogen dose to a maximum of 35 microgram Change progestogen if already taking an ethinyloestradiol 30–35 microgram pill Try another form of contraception. Consider the vaginal ring. Table 3 Risk of venous thromboembolism 19,20 Rate of venous thromboembolism per 10 000 women–years (10 000 women studied for one year) Non contraceptive users and not pregnant 2 Oral contraceptive users of pills 7–10 Pregnancy 29 Immediately postpartum 300–400 10 ARTICLE Full text free online at www.australianprescriber.com VOLUME 38 : NUMBER 1 : FEBRUARY 2015 Premenstrual syndrome and premenstrual dysphoric disorder Menstrual-related symptoms are commonly reported, but a proportion of women will experience more severe cyclic symptoms, known as premenstrual syndrome. A further subset of women will experience severe dysphoric symptoms, which have been labelled as premenstrual dysphoric disorder. Combined oral contraceptives, by regulating hormonal fluctuations, improve the physical symptoms of menstruation such as breast discomfort and primary dysmenorrhoea, but there is little evidence on their effect on mood and behavioural symptoms.33 The exception is the pill containing drospirenone 3 mg plus ethinyloestradiol 20 microgram, which may be more effective in treating severe premenstrual symptoms. Compared to placebo, it has been found to reduce impairment in productivity, social activities and relationships.34,35 Conclusion Contraceptive counselling should involve the provision of evidence-based information on the safety, efficacy, advantages and disadvantages of all methods of contraception. This enables women to make choices based on their personal preferences and medical suitability. All combined oral contraceptive pills in Australia have high efficacy provided they are taken regularly. There is little evidence for superior non-contraceptive benefits of the newer pills. The pills containing levonorgestrel or norethisterone in combination with ethinyloestradiol at doses equal to or below 35 microgram are considered first-line due to their possible lower risk of venous thromboembolism and their PBS listing. Other pills can be used if adverse effects develop, however 50 microgram pills are not recommended due to the risk of venous thromboembolism. Mary Stewart is employed by Family Planning NSW which conducts clinical trials sponsored by pharmaceutical companies. Family Planning NSW receives fees from MSD for contraceptive implant training and sponsorship from Bayer Healthcare for intrauterine device training sessions. Kirsten Black is a trainer on the implant insertion program supported by MSD. She is a consultant on an international advisory board for Bayer Healthcare and has received individual support to attend a conference as a presenter. Affordability Only the pills containing levonorgestrel and norethisterone are listed on the PBS (Table 1). The out-of-pocket expense for a four-month subsidised supply is approximately $20 compared to up to $120 or more for the newer non-PBS-listed pills. Non-contraceptive benefits There is not a great deal of evidence for the benefit of one pill type over another. Although the newer combined oral contraceptives have been marketed on their non-contraceptive benefits, it is important to understand which claims are well substantiated. Acne and hirsutism Most women with acne and hirsutism find that their skin improves when they take the combined oral contraceptive pill. This is in part because of a rise in sex hormone binding globulin. Pills containing cyproterone acetate, drospirenone, gestodene or desogestrel are often recommended, but the evidence for a benefit over levonorgestrel-containing pills is limited. The pills containing cyproterone acetate and ethinyloestradiol appear to improve acne (judged by inflammatory lesions and global assessments) better than those containing levonorgestrel.28 Studies comparing pills containing cyproterone acetate with pills containing drospirenone, gestodene or desogestrel have had conflicting results.29 Women with hirsutism may benefit from pills containing one of the anti-androgenic progestogens, including cyproterone acetate or drospirenone, which have been found to result in improvements in clinical hirsutism scores.30 Heavy menstrual bleeding All combined contraceptive pills can reduce the duration and heaviness of menstrual blood loss. Extending the days women take active pills while reducing or eliminating inactive pills can be useful for heavy menstrual bleeding. The oestradiol valerate with dienogest pill has a quadriphasic regimen which reduces menstrual blood loss through its effect on the endometrium. It has an indication for the management of heavy menstrual bleeding. This pill appears to be more effective at reducing the number of days of bleeding and the amount of blood loss when compared to combinations of ethinyloestradiol and levonorgestrel.10,31,32 Choosing a combined oral contraceptive pill SELF-TEST QUESTIONS True or false? 1. Users of the combined oral contraceptive pill have a higher cancer mortality rate than other women. 2. The risk of venous thromboembolism is higher with combined oral contraceptive pills containing 50 microgram ethinyloestradiol compared to those containing 35 microgram or less. Answers on page 35 11 ARTICLE Full text free online at www.australianprescriber.com VOLUME 38 : NUMBER 1 : FEBRUARY 2015 1. Mansour D, Inki P, Gemzell-Danielsson K. Efficacy of contraceptive methods: A review of the literature. Eur J Contracept Reprod Health Care 2010;15:4-16. 2. Rosenberg MJ, Meyers A, Roy V. Efficacy, cycle control, and side effects of low- and lower-dose oral contraceptives: a randomized trial of 20 micrograms and 35 micrograms estrogen preparations. Contraception 1999;60:321-9. 3. Gallo MF, Nanda K, Grimes DA, Lopez LM, Schulz KF. 20 µg versus >20 µg estrogen combined oral contraceptives for contraception. Cochrane Database Syst Rev 2011. CD003989. 4. Klipping C, Duijkers I, Trummer D, Marr J. Suppression of ovarian activity with a drospirenone-containing oral contraceptive in a 24/4 regimen. Contraception 2008;78:16-25. Erratum in: Contraception 2008;78:350. 5. Christin-Maitre S, Serfaty D, Chabbert-Buffet N, Ochsenbein E, Chassard D, Thomas JL. Comparison of a 24-day and a 21-day pill regimen for the novel combined oral contraceptive, nomegestrol acetate and 17β-estradiol (NOMAC/E2): a double-blind, randomized study. Hum Reprod 2011;26:1338-47. 6. Dinger J, Minh TD, Buttmann N, Bardenheuer K. Effectiveness of oral contraceptive pills in a large U.S. cohort comparing progestogen and regimen. Obstet Gynecol 2011;117:33-40. 7. Richters J, Grulich AE, de Visser RO, Smith AM, Rissel CE. Sex in Australia: contraceptive practices among a representative sample of women. Aust N Z J Public Health 2003;27:210-6. 8. Westhoff C, Kaunitz AM, Korver T, Sommer W, Bahamondes L, Darney P, et al. Efficacy, safety, and tolerability of a monophasic oral contraceptive containing nomegestrol acetate and 17β-estradiol: a randomized controlled trial. Obstet Gynecol 2012;119:989-99. 9. Fraser IS, Jensen J, Schaefers M, Mellinger U, Parke S, Serrani M. Normalization of blood loss in women with heavy menstrual bleeding treated with an oral contraceptive containing estradiol valerate/dienogest. Contraception 2012;86:96-101. 10. Fruzzetti F, Tremollieres F, Bitzer J. An overview of the development of combined oral contraceptives containing estradiol: focus on estradiol valerate/dienogest. Gynecol Endocrinol 2012;28:400-8. 11. Wiegratz I, Lee JH, Kutschera E, Winkler UH, Kuhl H. Effect of four oral contraceptives on hemostatic parameters. Contraception 2004;70:97-106. 12. Raps M, Rosendaal F, Ballieux B, Rosing J, Thomassen S, Helmerhorst F, et al. Resistance to APC and SHBG levels during use of a four-phasic oral contraceptive containing dienogest and estradiol valerate: a randomized controlled trial. J Thromb Haemost 2013;11:855-61. 13. Kalman SM. Effects of oral contraceptives. Annu Rev Pharmacol 1969;9:363-78. 14. Edelman AB, Gallo MF, Jensen JT, Nichols MD, Schulz KF, Grimes DA. Continuous or extended cycle vs. cyclic use of combined oral contraceptives for contraception. Cochrane Database Syst Rev 2005. CD004695. 15. Borgelt LM, Martell CW. Estradiol valerate/dienogest: a novel combined oral contraceptive. Clin Ther 2012;34:37-55. 16. Trussell J. Contraceptive failure in the United States. Contraception 2011;83:397-404. 17. 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Cardiovascular and general safety of a 24-day regimen of drospirenone- containing combined oral contraceptives: final results from the International Active Surveillance Study of Women Taking Oral Contraceptives. Contraception 2014;89:253-63. 24. Farley TM, Meirik O, Collins J. Cardiovascular disease and combined oral contraceptives: reviewing the evidence and balancin