Combined hormonal contraceptives

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Summary


Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks

Product information updated to help women make informed decisions about their choice of contraception

On 21 November 2013, the European Medicines Agency completed its review of combined hormonal contraceptives (CHCs), particularly of the risk of venous thromboembolism (VTE or blood clots in veins) associated with their use. The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) concluded that the benefits of CHCs in preventing unwanted pregnancies continue to outweigh their risks, and that the well-known risk of VTE with all CHCs is small.

The review has 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.

The product information of CHCs has been updated to help women make informed decisions about their choice of contraception together with their healthcare professional. It is important that women are made aware of the risk of VTE and its signs and symptoms, and that doctors take into consideration a woman’s individual risk factors when prescribing a contraceptive. Doctors should also consider how the risk of VTE with a particular CHC compares with other CHCs (see table below).

The review also looked at the risk of arterial thromboembolism (ATE, blood clots in arteries, which can potentially cause a stroke or heart attack). This risk is very low and there is no evidence for a difference in the level of risk between products depending on the type of progestogen.

The CHMP opinion, in agreement with the previous recommendation by the Pharmacovigilance Risk Assessment Committee (PRAC), was sent to the European Commission, which adopted on 16 January 2014 a legally binding decision to update the product information of all CHCs throughout the EU.

Information to patients
  • This Europe-wide review looked at the benefits and risks of combined hormonal contraceptives (CHCs), particularly the risk of blood clots associated with these medicines. It confirmed that the benefits of CHCs outweigh the risk of blood clots, which has been known for many years and is very low.
  • 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.
  • 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 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.
Information to healthcare professionals
  • The EU-wide review of combined hormonal contraceptives (CHCs) has confirmed that the known risk of venous thromboembolism (VTE) with all low-dose CHCs (ethinylestradiol < 50 mcg) is small.
  • Differences exist between CHCs in their risk of VTE depending on the type of progestogen they contain. Currently available data indicate that CHCs containing the progestogens levonorgestrel, norethisterone or norgestimate have the lowest risk of VTE (see table below).
  • When prescribing a CHC, careful consideration should be given to the individual woman’s current risk factors, particularly those for VTE, and the difference in risk of VTE between products. CHCs are contraindicated if a woman has one serious or multiple risk factors that put her at high risk of blood clots.
  • There is no evidence for differences between low-dose CHCs in their risk of arterial thromboembolism (ATE).
  • Because a woman’s individual risk factors will change over time, there is a need to regularly re-assess the suitability of her contraceptive.
  • It is also important to raise awareness of the signs and symptoms of VTE and ATE when prescribing a CHC.
  • Healthcare professionals should always consider the possibility of a CHC-associated thromboembolism when presented with a woman who has symptoms.
Risk of developing a blood clot (VTE) in a year
Women not using a combined hormonal pill/patch/ring and are not pregnantAbout 2 out of 10,000 women
Women using a CHC containing levonorgestrel, norethisterone or norgestimateAbout 5-7 out of 10,000 women
Women using a CHC containing etonogestrel or norelgestrominAbout 6-12 out of 10,000 women
Women using a CHC containing drospirenone, gestodene or desogestrelAbout 9-12 out of 10,000 women
Women using a CHC containing chlormadinone, dienogest or nomegestrolNot yet known1

1 Further studies are ongoing or planned to collect sufficient data to estimate the risk for these products.

More about the medicine

CHCs contain two types of hormones, an oestrogen and a progestogen. The review included all contraceptives containing low-dose oestrogen and the following progestogens: chlormadinone, desogestrel, dienogest, drospirenone, etonogestrel, gestodene, nomegestrol, norelgestromin and norgestimate. These are sometimes referred to as ‘third generation’ or ‘fourth generation’ contraceptives and are available as pills, skin patches and vaginal rings. During the review, the risk of VTE with these medicines was compared with that of CHCs containing levonorgestrel and norethisterone (also known as ‘second generation’ contraceptives).

The classification as ‘second, third or fourth generation’ is however not science-based and not standardised, and may differ between institutions and publications.

With the exception of Zoely (nomegestrol acetate/estradiol), Ioa (nomegestrol acetate/estradiol) and Evra (norelgestromin/ethinylestradiol), which have been authorised centrally through the EMA, all other combined contraceptives in the EU have been authorised via national procedures.

More about the procedure

The review of combined hormonal contraceptives was initiated in February 2013 at the request of France, under Article 31 of Directive 2001/83/EC.

A review of the data was first conducted by the Pharmacovigilance Risk Assessment Committee (PRAC), the Committee responsible for the evaluation of safety issues for human medicines, which made a set of recommendations. The PRAC recommendations were sent to the Committee for Medicinal Products for Human Use (CHMP), responsible for all questions concerning medicines for human use, which adopted the Agency’s final opinion.

The CHMP opinion was forwarded to the European Commission, which issued a final decision on 16 January 2014.

Name Language First published Last updated
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks BG = bălgarski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks ES = español 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks CS = čeština 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks DA = dansk 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks DE = Deutsch 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks ET = eesti keel 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks EL = elliniká 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks EN = English 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks FR = français 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks IT = italiano 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks LV = latviešu valoda 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks LT = lietuvių kalba 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks HU = magyar 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks MT = Malti 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks NL = Nederlands 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks PL = polski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks PT = português 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks RO = română 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks SK = slovenčina 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks SL = slovenščina 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks FI = suomi 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks SV = svenska 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks HR = Hrvatski 31/01/2014  

Key facts

About this medicine

Approved nameCombined hormonal contraceptives
International non-proprietary name (INN) or common name

desogestrel, gestodene, norgestimate, etonogestrel, drospirenone, dienogest, chlormadinone, nomegestrol, norelgestromin

Associated names-
Class-

About this procedure

Current statusEuropean Commission final decision
Reference numberEMEA/H/A-31/1356
TypeArticle 31 referrals

This type of referral is triggered when the interest of the Community is involved, following concerns relating to the quality, safety or efficacy of a medicine or a class of medicines.

Decision making modelPRAC-CHMP-EC
Authorisation modelCentrally and nationally authorised products (mixed)

Key dates and outcomes

Procedure start date07/02/2013
PRAC recommendation date10/10/2013
CHMP opinion/CMDh position date16/01/2014
OutcomeRisk minimisation measures

All documents

Recommendation provided by Pharmacovigilance Risk Assessment Committee

Name Language First published Last updated
PRAC confirms that benefits of all combined hormonal contraceptives (CHCs) continue to outweigh risks HR = Hrvatski 11/10/2013  
Combined hormonal contraceptives Article-31 referral - PRAC assessment report HR = Hrvatski 31/01/2014  

Opinion provided by Committee for Medicinal Products for Human Use

Name Language First published Last updated
Combined hormonal contraceptives Article-31 referral - CHMP divergent position to PRAC HR = Hrvatski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks – CHMP endorses PRAC recommendation HR = Hrvatski 22/11/2013  

European Commission final decision

Name Language First published Last updated
Combined hormonal contraceptives Article-31 referral - Annex I HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex I HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex I HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex I HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex I HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex I HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex I HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex I HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex I HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex I HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex I HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex I HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex I HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex I HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex I HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex I HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex I HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex I HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex I HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex I HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex I HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex I HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex I HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex I HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex I HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex IV HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex IV HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex IV HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex IV HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex IV HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex IV HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex IV HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex IV HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex IV HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex IV HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex IV HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex IV HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex IV HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex IV HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex IV HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex IV HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex IV HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex IV HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex IV HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex IV HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex IV HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex IV HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex IV HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex III HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex III HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex III HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex III HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex III HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex III HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex III HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex III HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex III HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex III HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex III HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex III HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex III HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex III HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex III HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex III HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex III HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex III HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex III HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex III HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex III HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex III HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex III HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex III HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex III HR = Hrvatski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks HR = Hrvatski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks HR = Hrvatski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks HR = Hrvatski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks HR = Hrvatski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks HR = Hrvatski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks HR = Hrvatski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks HR = Hrvatski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks HR = Hrvatski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks HR = Hrvatski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks HR = Hrvatski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks HR = Hrvatski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks HR = Hrvatski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks HR = Hrvatski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks HR = Hrvatski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks HR = Hrvatski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks HR = Hrvatski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks HR = Hrvatski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks HR = Hrvatski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks HR = Hrvatski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks HR = Hrvatski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks HR = Hrvatski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks HR = Hrvatski 31/01/2014  
Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex II HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex II HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex II HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex II HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex II HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex II HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex II HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex II HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex II HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex II HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex II HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex II HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex II HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex II HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex II HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex II HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex II HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex II HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex II HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex II HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex II HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex II HR = Hrvatski 31/01/2014  
Combined hormonal contraceptives Article-31 referral - Annex II HR = Hrvatski 31/01/2014  

Document description:

  • Annex I - List of the medicines affected by the referral
  • Annex II - Scientific conclusions of the Committee for Medicinal Products for Human Use (CHMP) or Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh)
  • Annex III - Changes to the summary of product characteristics, labelling or package leaflet - available when the CHMP or CMDh recommends changes to the product information. Also includes conditions for lifting of suspensions, if applicable
  • Annex IV - Conditions of the marketing authorisation - available when the CHMP or CMDh recommends other measures to be taken for the marketing authorisation such as safety measures or additional studies
  • Notification - A letter from a Member State, the European Commission or a marketing-authorisation holder requesting the initiation of a referral procedure
  • Rationale for triggering - Background provided by the party triggering the referral explaining the issues leading to the initiation of the procedure
  • PRAC list of questions - Questions agreed by the PRAC requesting further information to evaluate the issues identified
  • PRAC timetable - Timeframe agreed by the PRAC to receive information, assess the issues and adopt a recommendation
  • PRAC / CHMP / CMDh assessment report - The assessment and conclusions of the PRAC and CHMP or CMDh on the issues investigated

Current status:
European Commission final decision

More information on combined hormonal contraceptives