Contraception update

With so many forms of contraception available — and so much choice — it is difficult to keep up with what's new and the latest advice. Our round up of developments aims to help you catch up with recent product launches and current guidance

Since the introduction of the initial hormonal contraceptives there have been continuous developments making them more effective, more user-friendly and safer. Doses of hormones in the combined contraceptive pills used in the 1960s were the equivalent of seven pills used today.¹ Currently there are 15 different methods of contraception available in the UK, including both hormonal and non-hormonal methods, with a variety of different routes of administration allowing flexibility in choice depending on individual patient requirements.

The aim of this article is to provide an update on recent developments published by the Faculty of Sexual and Reproductive Health (FSRH) to ensure accurate, evidence based information can be given to patients ensuring they make the correct choice.

Topics covered

• Subcutaneous Depot Medroxyprogesterone Acetate (Sayana Press®)
• St. John's wort and hormonal contraception
• Progesterone only implants (Nexplanon®)
• Estradiol/Nomegestrol combined pill (Zoely®)
• Levonorgestrel-releasing intrauterine system (LNG-IUS) (Jaydess®)

SUBCUTANEOUS DEPOT MEDROXYPROGESTERONE ACETATE (SC DMPA) "” SANYANA PRESS®

Until recently injectable progesterone-only contraception was available as either the 8-weekly norethisterone enantate (Noristerat®) or the more commonly used 12-weekly medroxyprogesterone acetate (Depo Provera®), both of which require administration by deep intramuscular injection.

Sanyana Press®, which like Depo Provera contains medroxyprogesterone acetate (DMPA), is the first injectable progesterone-only contraception that is delivered by the subcutaneous route. It is not designed to replace Depo Provera but to offer an alternative option. Sanyana Press contains a slightly lower amount of DMPA (104mg compared to 150mg of Depo Provera) but studies have shown them to be equally effective, with no pregnancies being reported with Sanyana Press in 16,023 cycle uses,² and none in a randomised controlled trial over a three year period.³

The primary action of subcutaneous DMPA is the inhibition of secretion of gonadotrophins, thus preventing follicular maturation and ovulation. Suppression of follicular maturation results in lower oestrogen levels, and suppression of ovulation results in endometrial thinning.

The UK Medical Eligibility Criteria for Contraceptive Use (UKMEC),⁴ which sets agreed standards of safety for the available contraceptives, does not specifically include subcutaneous DMPA (SC DMPA). However, the FSRH Clinical Effectiveness Unit suggests that the UKMEC classification for intramuscular (IM) DMPA should be used.

Contraindications to, and cautions for use of, DMPA include:⁵

• Allergy to medroxyprogesterone acetate
• Pregnancy
• Known or suspected breast or genital malignancy
• Undiagnosed vaginal bleeding
• Severe hepatic impairment
• Metabolic bone disease
• Active thromboembolic disease or past medical history of cardiovascular disease

As when any new medication is initiated, the patient should be directed to relevant information sources, however the following areas should be discussed in detail with the patient prior to administration.

Effect on bleeding patterns

Most women will experience altered menstrual bleeding patterns, which may include intermenstrual bleeding, menorrhagia and metrorrhagia; however, 56.5% of users report being amenorrhoeic by the twelfth month of use. It is also essential to advise women of the potential for delay in return of fertility: in a small study of 39 patients who had just 1 dose of SC DMPA, fertility returned by 12 months in 97.4%, but the mean time to return to fertility was 30 weeks.⁶

Changes to bone mineral density (BMD)

SC DMPA reduces the levels of serum oestrogen, and this deficiency affects bone remodelling, which may subsequently cause significant loss of bone density (>5%). While this effect increases with longer duration of use, BMD does increase again once SC DMPA is stopped. It may however, take 1-3 years to return to baseline levels and particular attention should be paid to those women where oestrogen levels may not return to pre-use levels, such as peri-menopausal women.

Loss of BMD is a concern in adolescent or younger women (age 12 — 18) as this is a critical time for bone development. Peak BMD levels will not have been reached, and there is no current evidence to confirm whether this result in either a long-term reduction in peak bone mass or an increased risk of fractures in later life. It is therefore essential to assess the risks and benefits of DMPA, especially if it is to be used for more than two years. Relevant lifestyle advice on diet, exercise, alcohol and smoking should be given to all patients using DMPA.

In women with significant lifestyle or medical risk factors for osteoporosis, DMPA should only be used when other contraceptive methods have been fully considered.

Weight changes

Weight changes are common with SC DMPA but vary and are unpredictable.

The following figures have been reported:

• 50% remain within 2.2kg of their starting weight
• 12% lost more than 2.2% of their starting weight
• 38% gained more than 2.3% of their starting weight

Administration

Sayana Press is supplied as a single use pre-filled injector, which should be shaken vigorously and activated before use. The injection is given subcutaneously into the upper anterior thigh or abdomen and, to ensure full dosage, the injection should be given over 5-7 seconds, with the needle pointing downwards.

Currently SC DMPA has no license for self-administration and should therefore be given by a healthcare professional, although studies have shown self-administration to be feasible and acceptable to women,⁷ so this may come in the future.

First dose: SC DMPA should be administered within the first 5 days of the cycle when it gives immediate contraceptive cover. If administered at any other time, additional contraception should be used for 7 days.

Doses are repeated every 13 weeks, although the SPC states that if given within 14 weeks no extra contraceptive cover is required.

Post partum, the injection may be given within 5 days if not breastfeeding, but as with IM DMPA, prolonged and heavy bleeding may occur. If breastfeeding it should not be given before 6 weeks post-delivery.

If switching from another method of contraception, the injection should be administered in such a way as to ensure continuous cover is provided, where possible providing an overlap of 7 days.

ST JOHN'S WORT AND HORMONAL CONTRACEPTION

The Medicines and Healthcare Regulatory Agency (MHRA)⁸ has issued a warning on reduced contraceptive effect of hormonal contraception when used with the herbal preparation, St John's wort. It has also determined that all herbal medicinal products sold in the UK that fall under Directive 2004/24/EC require either a full marketing authorisation (MA) or a traditional herbal registration (THR) in order to remain on the market.

St John's wort is commonly used to relieve symptoms of low mood and anxiety. However, it has enzyme-inducing effects on the cytochrome P450 enzymes that result in reduced efficacy of certain other medications if co-administered.

Following a total of 19 'Yellow Card' reports of unplanned pregnancies in women using hormonal contraceptives, including two with progestogen-only implants suspected to be the result of an interaction with St John's wort, the MHRA recommends that women who use the herbal remedy should be offered an alternative form of contraception.⁸

The FSRH⁹ advises that:

• Women using combined hormonal contraceptives, progestogen-only pills, oral emergency contraception or the progestogen-only implant require alternative or additional contraception when taking enzyme-inducing drugs, including St John's wort.
• Drugs that induce hepatic enzymes are unlikely to affect the pharmacokinetics of DMPA
• Most of the contraceptive effect of the Levonorgestrel-releasing intrauterine system (LNG-IUS) is mediated via the direct release of progestogen into the uterus, and is therefore presumed to be unaffected by metabolism in the liver.

The take home message here, as with all prescribing practice, is that it is essential to check for concurrent use of alternative therapies including herbal preparations.

PROGESTERONE ONLY IMPLANTS (NEXPLANON®)

Nexplanon® has been available since 2010, when it replaced a similar long-acting reversible contracteptive, Implanon®. It is currently the only progesterone-only implant (POI) available in the UK. Recent FRSH guidance on Nexplanon offers updated advice on:

• Changes to advice on switching from different methods of contraception
• Modified guidance in relation to body weight timing of replacement
• Information on insertion and removal
• Updated advice on damaged or impalpable implants

For details relating to the product and fitting, the summary of product characteristics (SPC) should always be referred too and guidance relating to safety in specific patient groups can be found in the UKMEC guidelines available from www.fsrh.org.

The FSRH has issued updated guidance on when the POI can be fitted and the circumstances that warrant additional contraception. (Table 1)¹⁰

POI should not be fitted without a full assessment of the risk of pregnancy. If unprotected sexual intercourse (UPSI) has occurred, it must be assumed that pregnancy is possible, and the POI should not be fitted until a pregnancy test, done at least 3 weeks after the last UPSI, is negative. However, the FSRH 'quick start' information gives more details on when fitting may be acceptable outside these conditions.¹¹

The guidance on switching from one form of hormonal contraception to another is based on consistency across the FSRH guidelines rather than evidence, as there are no studies that have assessed maintenance of contraceptive cover when changing from one form of contraception to another.

With so many different hormonal forms of contraception and so many different situations you should refer to the specific FSRH guideline to ensure no breaks in contraceptive cover and that the advice you give when counselling women is accurate.

POI and obesity

There is no restriction on the use of POI in women with a BMI >30kg/m² (UKMEC 1 category). However, the contraceptive effect of POI is related to the plasma levels of etonogestrel, which are inversely related to body weight, and which decrease with time after insertion. The manufacturers therefore suggest that earlier replacement is considered in heavier women, although there is very little reliable evidence to demonstrate either failure rates associated with replacement at standard 3 year intervals. The FSRH recommends explaining to the woman that a reduction in efficacy cannot be excluded in the third year of use and that early replacement may be considered, depending on the woman's bleeding patterns and previous known fertility.¹⁰

Nexplanon® is radio-opaque, i.e. it is radiologically detectable in situations where the implant is non-palpable. Suitable methods for localisation of the implant include CT or MRI scanning, but in general practice, ultrasound scanning is the preferred method of detection. Blind exploratory surgery is 'strongly discouraged'. If there is any doubt that the implant is in situ, additional contraception should be used until correct placement is confirmed.¹²

ESTRADIOL/NOMEGESTROL COMBINED PILL (ZOELY®)

Zoely® is a new monophasic combined pill containing estradiol1.5mg and nomegestrol 2.5mg.¹³ It joins Qlaira® (quadraphasic) as another estrodiol-containing pill. Its main mode of action is by gonadotrophin suppression thus inhibiting ovulation. The pack contains 24 active pills and 4 inactive pills, so it is taken daily with no pill-free interval. Bleeding usually starts 2-3 days into the non-active pill period.

If started on the first day of the menstrual cycle, on the day of, or day after first trimester termination, on the day after the last active pill of a previous COC or between day 21 and 28 following delivery or second trimester termination, Zoely is effective immediately. If started at any other time or when changing from any progesterone only method, additional contraception is required for 7 days.

The efficacy of Zoely is comparable to that of Yasmin® (drospirenone and ethinylestradiol) and tolerability and safety appear to be similar, although the incidence of no withdrawal bleed appears to be higher, and lipid and glucose metabolism seem to be affected less than with other COCs. The FSRH guidance is to use Zoely in a similar way to other COCs.

Zoely can be taken continuously to avoid a withdrawal bleed by missing the 4 inactive pills and continuing without a break with the next pack.

Restrictions on Zoely use are comparable with other COCs: see UKMEC guidance for more details.

Missed or late pill rules are specific to timings and therefore the SPC should be consulted for accurate guidance.

LEVONORGESTREL-RELEASING INTRAUTERINE SYSTEM (LNG-IUS) (JAYDESS®)

Until very recently, there has only been one levonorgestrel-releasing intrauterine system (LNG-IUS) available in the UK — Mirena®. However, a new version containing a lower dose of levonorgestrel came to market earlier this year — Jaydess®. Jaydess contains only 13.5mg levonorgestrel, compared with 52mg in Mirena.¹⁴ This means that the daily dose is also lower, 14mcg in 24 hours for the first 24 days after insertion, reducing to an average of 6mcg/24hours over 3 years, the lowest average dose of hormones of any long-acting reversible contraceptive method.

The contraceptive efficacy is estimated at more than 99%, and the IUS can be left in place for 3 years (compared with 5 years for Mirena). It works by suppressing endometrial proliferation, which also has the effect of reducing the duration and volume of menstrual bleeding: scanty flow frequently develops into oligomenorrhea or amenorrhea, but ovarian function — and therefore, future fertility — are unaffected.

Although the device is smaller than the Mirena IUS, and therefore presumed to be more comfortable on insertion, it is not yet recommended for nulliparous women due to lack of clinical experience.

The FSRH has reviewed this product, but has yet to issue formal guidance.¹⁴

CONCLUSION

With so many contraceptive choices available maintaining up to date knowledge on new contraceptive products is essential to ensure the patient receives a high quality service allowing an informed choice of product. Remember a dual protection approach — i.e. the use of condoms to protect against sexually transmitted infections — may also be appropriate.

REFERENCES

1. Family Planning Association (2013). Contraception — past, present and future. Available at: http://www.fpa.org.uk/factsheets/contraception-past-present-future

2. Kaunitz AM, Darney PD, Rodss D, et al. Subcutaneous DMPA vs intramuscular DMPA: a 2 year randomised study of contraceptive efficacy and bone mineral density. Contraception 2009; 80(1);7-17

3. Jain J, Jakimuiuk A.J, Bode D, Kaunitz A.M (2004) Contraception efficacy and safety of DMPA-SC. Contraception 2004;70(4):269-75

4. Faculty of Sexual and Reproductive Health Clinical Guidance (2009) The UK medical eligibility criteria for contraception Available at: http://www.fsrh.org/pdfs/UKMEC2009.pdf

5. Pfizer Ltd. (2014) Medroxyprogesterone Acetate (Depo Provera®). Available at: http://www.medicines.org.uk/emc/medicine/11121/SPC/Depo-Provera

6. Faculty of Sexual and Reproductive Health Clinical Guidance (2013) Subcutaneous Depot Medroxyprogesterone Acetate (Sayana Press®). Available at: http://www.fsrh.org/pdfs/CEUProductReviewSayana.pdf

7. Prabhakaran S, Sweet A. Self administration of subcutaneous depot medroxyprogesterone acetate for contraception: feasibility and acceptability, Contraception 2012;85(5):453-7

8. Medicines and Healthcare Regulatory Agency

(2014). Herbal medicines regulation. Available at: http://www.mhra.gov.uk/Howweregulate/Medicines/Herbalmedicinesregulation/

9. Faculty of Sexual and Reproductive Healthcare Clinical Guidance (2014). St John's wort and hormonal contraception. Available at: http://www.fsrh.org/pdfs/CEUStatementStJohnsWort.pdf

10. Faculty of Sexual and Reproductive Health Clinical Guidance (2014) Progesterone-only implants. Available at: http://www.fsrh.org/pdfs/CEUGuidanceProgestogenOnlyImplants.pdf

11. Merck Sharpe & Dohme (2014) Nexplanon: Summary of Product Characteristics. Available at:http://www.medicines.org.uk/emc/medicine/23824/SPC/nexplanon

12. Faculty of Sexual and Reproductive Healthcare Clinical Guidance (2010) Quick Starting Contraception. Available at: http://www.fsrh.org/pdfs/CEUGuidanceQuickStartingContraception.pdf

13. Merck Sharp & Dohme (2014) Zoely: Summary of Product Characteristics. Available at: http://www.medicines.org.uk/emc/medicine/27581/SPC/Zoely/

14. Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness Unit. New product Review. Jaydess® levonorgestrel intrauterine system (LNG-IUS).(April 2014). Available at: http://www.fsrh.org/pdfs/CEUProductReviewJaydess.pdf