Safe Prescribing of the Oral Contraceptive

Up to date redacted information from references below regarding oral contraception.

Among the most feared complications associated with oral contraceptive pill (OCP) use (and menopausal hormone therapy), venous thromboembolic events (VTE) typically manifest as deep venous thrombosis (DVT), with its more serious risk for pulmonary embolism but also its potential for chronic venous disease. But the spectrum of VTEs also includes upper extremity and intraabdominal DVT, cerebral sinus thrombosis (venous stroke), and superficial venous thrombophlebitis. Population based studies show that the annual incidence of VTEs increases from 1 in 100,000 persons younger than 20 years old to 1 in 10,000 persons aged 20-40 years, to 1 in 1000 persons aged 41-75 years, and 1 in 100 persons older than 75 years.

Annual incidence of VTE by age:

• < 20 years old: 1 in 100,000
• 20-40 years old: 1 in 10,000
• 41-75 years old: 1 in 1000
• > 75 years old: 1 in 100

Any exposure, therefore, that increases the relative risk of VTEs will result in greater absolute risk and will likely be of greater clinical significance in older rather than young persons.

Absolute contraindication to OCP:

• Thromboembolic disease
• CAD
• Cerebrovascular accident
• Active liver disease
• Oestrogen dependent malignancy
• Focal migraine
• Porphyrias
• Pregnancy

Relative contraindication to OCP:

• HTN
• DM
• > 35 years + risks CAD
• Previous cholestasis
• Undiagnosed vaginal bleeding
• Elective surgery within 4 weeks
• Sickle cell disease
• Severe depression

Drug Interactions

Combined Contraceptive Pills and Liver-Inducing Medications

Hepatic enzyme inducing drugs can lead to OCP failures, especially in those women taking low-dose COCs. Women on anti-epileptic drugs (AEDs) such as phenytoin, carbamazepine, or primidone, who want to take an OCP, should be prescribed the higher dose (50 mcg) oestrogen contraceptive pill. When these women take certain antibiotics, additional precautions against pregnancy, such as barrier method, should be taken.

Higher doses of oestrogen and extended regimens are necessary to give a contraceptive effect when the combined contraceptive pill is used in long-term users of liver enzyme-inducing medications. These women should take daily either two 30 μg ethinyloestradiol-containing pills, or one 20 μg plus one 30 μg ethinyloestradiol-containing pill, and run together three cycles (63 days) of active pills only from three packets (i.e. without placebo pills), and have a four-day placebo break after each three-packet cycle of 63 active pills

Timing A Start to the Pill

The combined contraceptive pill, vaginal ring, or progestogen-only pill will be effective immediately when:

• started on day 1 – 5 of a normal menstrual cycle
• started on day 1 – 5 of the menstrual cycle in women previously using a copper or hormonal IUD and having a regular menstrual cycle
• changing from a contraceptive implant inserted in the previous three years or a DMPA injection given in the previous 14 weeks
• started within five days of a termination or miscarriage.

The combined contraceptive pill is only immediately effective if initiated with an active pill tablet. Combined hormonal contraceptives (CHCs) offer several advantages, including a beneficial effect on acne, a decrease in menstrual pain and bleeding, and an ability to manipulate menstrual cycles. They also decrease the risk of ovarian, endometrial, and bowel cancer.

 The UK Medicines and Healthcare products Regulatory Agency (MHRA) identified a need for clearer, more consistent, missed pill rules. New missed-pill advice approved by the FSRH and the Family Planning Association (FPA) apply to all combined oral contraceptives (COCs) with an estrogen dose of at least 20 μg (with the exception of the estradiol valerate-containing pill, Qlaira), whether monophasic or phasic and including every day preparations. Pharmaceutical companies marketing COCs made amendments to their patient information leaflets in line with CHM advice. The CEU provides guidance on combined hormonal contraception, including advice on how to deal with incorrect use of the combined patch and combined vaginal ring.

Initiating the progestogen-only pill

Progesterone-only pills (POPs) or “minipills” can be initiated in women of any age, and can be used until menopause if there are no contraindications. All POP packs have 28 active pills and no placebo pills. POPs are immediately effective in the same situations as CHCs, and also when initiated immediately after delivery. In most other situations, they are effective after three tablets have been taken.

Fine Tuning for Side Effects of Oral Contraceptives

Lighter bleeding is a feature of most hormonal contraceptive methods and simply reflects suppressive effect of progestogen on endometrium. In some women, this is so profound, however, that cyclical bleeding disappears completely; especially those using depo-medroxyprogesterone (DMPA) and levonorgestrel-releasing IUDs, in which about 50-80% of women are amenorrheic at 12 months. Those women taking newer oestradiol pills (Qlaira, Zoely)  will not have regular withdrawal bleeds, since these pills rely on potent endometrial suppression to achieve cycle control.

Hormone-withdrawal side effects include pain, headache, breast tenderness, and bloating. Most effects of the OCP are transient for the first few months and subside over time. Importantly, women who have a hormonal IUD may return to fertility instantaneously after its removal; although may take a few months to return to normal cycling when combined contraception is used.

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.

Side Effects and their Management:

• Nausea and vomiting:
  • exclude pregnancy
  • reduce oestrogen dose
  • take pills at night
  • change to a progestogen-only method
• Weight gain: Change progestogen
• Bloating and fluid retention:
  • reduce oestrogen dose
  • change to progestogen with mild diuretic effect (i.e. drospirenone)
• Cyclic weight gain: Reduce oestrogen
• Chloasma:
  • avoid sun exposure
  • use SPF 15 sunscreen
  • stop oestrogen and try a progestogen-only pill
• 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
• Breast tenderness:
  • reduce oestrogen and/or progestogen dose
  • change progestogen
    • consider using a pill containing drospirenone
• Acne:
  • increase oestrogen
  • change progestogen
• Headache:
  • reduce oestrogen dose and/or change progestogen
  • if headache occurs in a hormone-free week, consider:
    • extended use, or
    • giving oestradiol 50 microgram transdermal patch in this week, or
    • try oestradiol valerate/dienogest pill
• Dysmenorrhoea: Extended pill regimen to reduce the frequency of bleeding
• Pill amenorrhoea:
  • increase oestrogen
  • decrease progestogen
• Decreased libido: no evidence supports a benefit of one type of oral contraceptive pill over another.[1]

Missed Pill Recommendations

If it is reasonably certain that the woman is not pregnant, COCs can be initiated on any day of the menstrual cycle, not just the first day. Additional contraceptive precautions are required for the first 7 days if the pills are started after Day 5 of the cycle. If one active pill is missed, there is no need to take additional precautions. Where two active pills are missed, additional precautions should be taken for the next 7 days.[2]

Missed Combined Oral Contraceptive Pill (COCP): is the pill more than 24 hours overdue?

Missed Combined Oral Contraceptive Pills (COCP): CEU advice for health professionals

Missed Progesterone-only Contraceptive Pill (POP): is the pill more than 3 hours overdue?

Extended Cycling

In practice, women with pre-existing risk factors for venous or arterial disease, which make the COC an unsafe option, still have progestogen-only or non-hormonal highly effective methods to choose from. Conversely, women with no contraindications to the use of oestrogen can potentially use any of the available COCs with choice being determined by side-effects, additional non-contraceptive benefits, cost, and personal preference. Increasing awareness and uptake of long-acting reversible contraceptive (LARC) methods are likely to impact the proportion of women using the COC, though many women will continue to choose an oral method of fertility control. There have been significant changes to COC formulations over the past 50 years, including the development of progestogens with anti-androgenic activity and positive benefits on hormone-mediated bleeding, and the replacement of ethinyloestradiol with oestradiol. Future developments in hormonal contraception, however, will more likely relate to alternate delivery systems, especially delivery systems that can be self-administered or minimises contact with the health system. For two-thirds of Australian women are extended cycling with the OCP, presumably for means of convenience. A Cochrane Review says that extended cycling is not dangerous and may be beneficial in some.

Combined contraceptive pills and vaginal rings can be used continuously without a placebo break, with rings being replaced up to four-weekly. This regimen may be chosen for convenience or to avoid symptoms associated with the withdrawal bleed. There is no upper limit to the number of placebo breaks a woman can miss, provided she remains amenorrhoeic. Although many women achieve amenorrhoea with continuous use of CHCs, unscheduled bleeding can be a problem. This bleeding is best managed by taking a placebo break of four to seven days at any time, provided the woman has taken at least 24 pills previously.

Background

The first combined oral contraceptive pill (COC) marketed in 1961 contained high doses of oestrogen and progestogen hormones and were associated with a relatively high risk of venous thromboembolic (VTE), arterial disease, and likelihood of unwanted side-effects, such as nausea and breast tenderness. The risks have been reduced by the development of COCs with lower doses of oestrogen and an awareness of safe prescribing, taking a woman’s risk factors into account. Guidelines for the safe provision of contraception include the World Health Organisation Medical Eligibility Criteria (MEC) and UK-based MEC guidelines from the Faculty of Sexual and Reproductive Health (FSRH). In Australia, a variety of OCPs are available. These range from low- to high-dose oestrogen, monophasic or multiphasic preparations and, while they have limited variety in terms of oestrogen, there is considerably more variety in the progestogen used.

COCP types in Australia (not all generics included). Newer pills contain oestradiol or its valerate salt where older pills used ethinyl oestradiol.

Newer progestogens were subsequently developed in an attempt to minimise androgenic and other troublesome effects, while the dose of ethinyl oestradiol was reduced to potentially lower the VTE risk and oestrogenic side effects, such as nausea and breast tenderness. Nevertheless, all currently available COCs have an effect on metabolic parameters, including oestrogen-related increases in Sex Hormone Binding Globulin (SHBG), Corticosteroid-Binding Globulin (CBG), angiotensinogen, apolipoprotein A1, and a change in various coagulation and fibrinolysis factors, all parameters modulated by the combination and dose of oestrogen and progestogen in a given pill type. The effects of hormonal combinations on metabolic markers for vascular disease do not, however, always directly translate into disease outcomes, and controversy continues about the modulating effect of progestogen type on VTE risk. The dose effect of ethinyloestradiol on VTE risk is clearer; however, with today’s low-dose COCs containing 35mcg of EE or less, pose a low VTE risk when appropriately prescribed. Since 2010, COCs containing either 17β–oestradiol or its prodrug, oestradiol valerate, in place of ethinyloestradiol have been available. These oestrogens are structurally identical to the 17β–oestradiol (E2) produced by the ovary. In the laboratory setting, COCs with 17β-oestradiol or oestradiol valerate perform favourably compared with ethinyloestradiol pills in relation to their effect on coagulation factors and insulin resistance. It may nonetheless take some years, until the maturity of post-marketing surveillance studies on these newer pill formulations, to see if these theoretical but unproven benefits in terms of venous thromboembolism risk translate into improved health outcomes.

The Oestrogen Component of COCs

The majority of COCs marketed in Australia contain the potent synthetic steroid ethinyloestradiol (EE) with, courtesy of its 17α–ethinyl group, a pronounced effect on hepatic metabolism. Today’s low-dose COCs contain 35 mcg or less of ethinyloestradiol. It is unknown whether the lowest dose pill formulations available in Australia, those with 20mcg EE, offer a safety benefit over those with 35 or 30mcg ethinyloestradiol and any potential safety advantage must be offset by an increased chance of unpredictable breakthrough bleeding.

The Progestogen Component of COCs

While progesterone itself cannot be used in the COC due to its rapid liver metabolism, the synthetic progestogens in COCs are structurally related either to progesterone (pregnanes) or to testosterone (estranes and gonanes). Several newer progestogens have been developed to bind more selectively to the progesterone receptor while minimising androgenic, oestrogenic, and/or glucocorticoid receptor interactions and their potential side-effects. The earliest progestogens, levonorgestrel (LNG) and norethisterone (NET), are derived from testosterone, while later progestogens are derived from progesterone or its related mineralocorticoid, spironolactone. Early common side effects, such as nausea, breast tenderness, headaches, fluid retention and altered mood or bleeding pattern, are common in the first month as the body adjusts to the introduction of synthetic hormones and the altering of endogenous hormone secretion. These generally settle in most women over successive cycles. The most androgenic progestogens may be associated with impaired glucose tolerance and increased insulin resistance, both risk factors for cardiovascular disease and Type II diabetes mellitus. Again, evidence for clinically relevant differences between progestogen types is lacking and the use of COCs in women with polycystic ovarian syndrome (PCOS) has not, for example, been found to be associated with clinically significant adverse metabolic consequences.

In relation to this progestogen component of the COC, earlier laboratory and registry studies suggest that pills with levonorgestrel (LNG) are associated with a lower VTE risk than those containing newer progestogens. Later large, well-designed cohort studies, however, have not confirmed a difference in risk between progestogen types. A recent controlled, prospective, observational, active surveillance study of more than 85,000 women that compared a COC containing 30 mcg ethinyloestradiol and drospirenone in an extended 24-day regimen to other commonly used COCs in a routine clinical setting supports a lack of difference in the risk of serious adverse cardiovascular events between available COC types. While all large database studies may be prone to bias, it is nevertheless reasonable to conclude that a woman’s own underlying risk factors for VTE or arterial vascular disease have a much more significant impact on her risk than any differences between product constituents.

Contraception when Approaching the Menopause

The possibility of women between 45-49 years falling pregnant is estimated at 2-3%. The risk of pregnancy without contraception after the age of 50 years is minimal, less than 1%. Most women using contraception when approaching menopause find they have more regular periods with less blood loss during their periods. Their period pain is often less severe. The Pill, moreover, reduces their risk of ovarian and endometrial cancer. But, of course, the Pill comes not without risk, in particular for:

• blood clots in the legs or lungs, heart attack, stroke, and benign liver tumours
  • smokers over 35 years of age should not use the combined Pill because the risk of clotting is increased further still
• breast cancer: under investigation and no clear answer has been found
• unsuitable for women with migraines, especially “focal” migraines
• may mask the onset of menopause and make it hard to know when to stop taking it

COCs marketed in Australia

References

1. Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness Unit. “Missed Pill Recommendations.” CEU Statement. Faculty of Sexual and Reproductive Healthcare (FSRH), May 2011.
2. Gomes, Marcelo P. V. Deitcher, Steven R. “Risk of Venous Thromboembolic Disease Associated With Hormonal Contraceptives and Hormone Replacement Therapy.” Arch Intern Med 164; 2004: 1965-1976.  www.archinternmed.com.
3. Gordon, P. “Anti-epileptic medications.” O&G Magazine 16(2); 2014: 14-6.
4. McNamee, Kathleen; Harvey, Caroline and  Bateson, Deborah. A practical guide to contraception. Part 1: Contraceptive pills and vaginal rings.” Medicine Today 14(7); 2013: 18-32.
5. Stewart, Mary; Chaar, Betty and Bateson, Deborah. “Combined oral contraceptives: The pharmacology of combined oral contraceptive pills old and new.” O&G Magazine 16(2); 2014: 14-17.
6. Weisberg, Edith. “Oral Contraceptive: Fine Tuning Clinical Guide.” Patient Management. Feb 1997.
7. Aus Prescr 48(1); 2015, 7 and 9.

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Further: Electronic Medicines Compendium (emc).