In 2013, the European Medicines Agency (EMA) completed a review of certain combined hormonal contraceptives (CHCs) authorised in the European Union (EU).
The two committees in involved in this procedure, the Pharmacovigilance Risk Assessment Committee (PRAC) and the Agency’s Committee for Medicinal Products for Human Use (CHMP), both concluded that the benefits of CHCs in preventing unwanted pregnancies continue to outweigh their risks, and that the well-known risk of venous thromboembolism (VTE) with all CHCs is small. The review reinforced the importance of ensuring that clear and up-to-date information is provided to women who use these medicines and to the healthcare professionals giving advice and clinical care.
Advice for women:
- If you have been taking CHCs without any problem, there is no reason for you to stop taking them on the basis of this review. But it is important that you are aware of the risk of blood clots associated with these medicines, even though it is very low.
- The risk of blood clots in the veins varies between CHCs, depending on the type of progestogen (a hormone) they contain, and ranges from 5 to 12 cases of blood clots per 10,000 women who use them for a year (see table below). This compares with 2 cases of blood clots in the veins each year per 10,000 women who are not using CHCs.
- You should also be aware of the factors that increase your risk of a clot and be aware of how these may change over time. Risk factors include, among others, being very overweight, increasing age, having a member of your family who has had a blood clot at a relatively young age (e.g. below 50), having migraine or being immobilised for a long time (e.g. because of an illness or injury). Your risk of a blood clot is higher in the first year of using a CHC.
- You should discuss with your doctor or nurse what is the most appropriate type of contraception for you.
- When taking CHCs, you should be alert for the signs and symptoms of blood clots, which may include severe pain or swelling in the legs, sudden unexplained breathlessness, rapid breathing or cough, chest pain, and weakness or numbness of the face, arm or leg. If you develop any of these signs and symptoms you should seek medical advice immediately.
- If you have any questions or concerns, speak with your doctor, pharmacist or nurse.
A letter will be sent to healthcare professionals across the European Union (EU) informing them of the outcome of this review and of the new recommendations for use of these medicines.
Product information for these medicines will be updated to help women make informed choices about their choice of contraception.
The CHMP also concluded that the risk of VTE with different CHCs differs between products depending on the type of progestogen they contain.
Risk of developing a blood clot (VTE) in a year
|Women not using a combined hormonal pill/patch/ring and are not pregnant||About 2 out of 10,000 women|
|Women using a CHC containing levonorgestrel, norethisterone or norgestimate||About 5-7 out of 10,000 women|
|Women using a CHC containing etonogestrel or norelgestromin||About 6-12 out of 10,000 women|
|Women using a CHC containing drospirenone, gestodene or desogestrel||About 9-12 out of 10,000 women|
|Women using a CHC containing chlormadinone, dienogest or nomegestrol||Not yet known*|
* Further studies are ongoing or planned to collect sufficient data to estimate the risk for these products.
The risk of arterial thromboembolism (ATE) with CHCs was also investigated and no evidence was found for differences in the risk between individual progestogens.
In January 2014, the European Commission adopted a legally-binding decision to update the product information of all CHCs throughout the EU.
- For more information on the scientific opinion see Combined hormonal contraceptives.
What are combined hormonal contraceptives?
CHCs contain two types of hormones, an oestrogen and a progestogen. The review includes contraceptives containing the following progestogens: chlormadinone, desogestrel, dienogest, drospirenone, etonogestrel, gestodene, nomegestrol, norelgestromin and norgestimate.
The CHCs being reviewed are sometimes referred to as ‘third-generation’ or ‘fourth-generation’ contraceptives and are available as pills, skin patches and vaginal rings. The current review is assessing the risk of thromboembolism with each progestogen individually.
Generations of hormonal contraceptive products – a history
Hormonal contraceptives are sometimes classified by ‘generations’, reflecting the point in time when they were developed and authorised for use.
- The first generation of contraceptive pills, developed in the 1960s, used a high concentration of oestrogen with no progestogen component.
- Later, a second generation of hormonal contraceptive was introduced. These medicines combined lower levels of oestrogens with various progestogens in different concentrations, often levonorgestrel.
- Since the 1990s, further combined hormonal contraceptive products have been developed. They contain different progestogens from those used in second-generation products, with similar contraceptive effect. These newer products are sometimes referred to as third- and fourth-generation contraceptives.
This classification is not science-based and not standardised, and may differ between institutions and publications.
There are also hormonal contraceptives that contain a progestogen only, and these products fall outside the scope of this referral.
Background on the current review of CHCs
The review of CHCs was initiated at the request of France in February 2013 following concerns about the risk of VTE and possible fatal pulmonary embolism with these medicines. The review also covered the risk of arterial thromboembolism (blood clots in arteries), which can potentially cause a stroke or heart attack.
The PRAC reviewed all available data on the risk of VTE and ATE with the CHCs listed above. The Committee examined data gathered from marketing authorisation holders, drug utilisation studies, and published literature, as well as cases of thromboembolism reported by patients and healthcare professionals. Experts were convened specifically to discuss this issue and presented their views to the PRAC. All information was considered as part of the review. The PRAC recommendations were sent to the CHMP, which agreed with the PRAC’s position and adopted the Agency’s final opinion.
Previous EMA reviews
Previous EMA reviews of combined oral contraceptives concluded that their absolute risk of VTE is low, and information on the risk and its management is included in their product information. Previous reviews did not examine the risk of ATE associated with these medicines.
Oral combined hormonal contraceptives: reviewed in 2001
In 2001, the EMA’s scientific committee then called the Committee for Proprietary Medicinal Products (CPMP) concluded an assessment on the risk of VTE associated with the use of so-called third generation combined oral contraceptives containing the progestogens desogestrel or gestodene.
The review began in 1995 and was based on three independent epidemiological studies that indicated an increased risk of VTE for these products, compared to combined oral contraceptives containing the progestogen levonorgestrel. The EMA issued public statements in 1995, and also, taking into account newly-emerging data, in 1996 and 1997. Further to the initial studies, the 2001 review evaluated additional epidemiological studies and studies on blood clotting mechanisms, and concluded the following on the small increased VTE risk of the so-called third generation products:
- CPMP concludes its assessment of 'third-generation' combined oral contraceptives and the risk of VTE
Drosperinone-containing CHCs: last reviewed in 2012
In 2012, the CHMP Pharmacovigilance Working Party (PhVWP) – now superseded by the PRAC - completed an informal review of two new epidemiological studies regarding the risk of VTE associated with oral drospirenone-containing CHCs. As these products only became available after 2001, they were not included in the 2001 review.
The findings of these studies confirmed the conclusion of a review of these products by PhVWP in May 2011 that the risk of VTE with any oral CHC (including those containing drospirenone) is low. The risk for drospirenone-containing products is higher than for those containing levonorgestrel and may be similar to the risk for those containing desogestrel or gestodene (so-called third generation CHCs).
For more information on the conclusions of the PhVWP to national competent authorities, see:
Diane 35 and generics
The PRAC has also recently conducted a separate review of Diane 35 (cyproterone acetate 2 mg, ethinylestradiol 35 micrograms) and its generics – a treatment for acne and other hormone-related conditions. The progestogen content of Diane 35, cyproterone, supresses ovulation and therefore also has a contraceptive effect, although it is not authorised as a contraceptive in its own right.
In May 2013, the PRAC concluded that the benefits of Diane 35 and its generics outweigh the risks, provided that several measures are taken to minimise the risk of thromboembolism. These medicines should be used solely in the treatment of moderate to severe acne related to androgen sensitivity or hirsutism (excessive unwanted growth of hair in women) in women of reproductive age. Furthermore, Diane 35 should only be used for the treatment of acne when alternative treatments, such as topical therapy and oral antibiotic treatment, have failed.
Since Diane 35 and its generics acts as hormonal contraceptives, women should not take these medicines in combination with other hormonal contraceptives. Concomitant use of Diane 35 and its generics with another hormonal contraceptive will expose women to a higher dose of oestrogen and increase the risk of thromboembolism.
Following the adoption of the European Commission decision on Diane 35 in July 2013, the PRAC’s recommendation is now being implemented across EU Member States.
- For more information on this review, see Cryproterone- and ethinylestradiol- containing medicines.
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