European Medicines Agency has started the review of third- and fourth-generation combined oral contraceptives
30.01.2013
Due to a recent initiative to reduce the use of third- and fourth-generation combined oral contraceptives, the European Medicines Agency has been requested by France to review the benefits risks ratio of third- and fourth-generation (so called "newer" combined oral contraceptives) combined oral contraceptives. The review of benefits risks ratio is being carried out in order to determine whether there is a need to restrict the use of these medicinal products to women who cannot take other combined oral contraceptives. The EMA’s Pharmacovigilance Assessment Committee (PRAC) will be reviewing whether the currently available product information on combined oral contraceptives provides the best information possible for patients and doctors to take appropriate healthcare decisions. New information about the review by the PRAC will be available by the end of next week. According to EU legislation, the final recommendation by PRAC about the use of third- and fourth-generation oral contraceptives may be expected in the period from 30 to 90 days, except for cases, when upon Chair’s request, the recommendation may be adopted sooner, if estimated as an exceptional safety issue.
Risks of venous thromboembolism associated with the use of oral contraceptives
A venous thrombosis is a blood clot that forms within a vein, which by circulation may be transported into the lungs and lead to a thrombosis of lungs blood vessels, which means embolism. It is known that combined oral contraceptives carry a risk of venous thromboembolism that rarely occurs with the use of those medicines. The absolute risk of venous thromboembolism with the use of combined oral contraceptives is very low and smaller than the risk of venous thromboembolism associated with pregnancy. The risk of venous thromboembolism is between 20 and 40 cases out of 100 000 women during the one year of use and it differs for oral contraceptives of different generations. The risk of venous thromboembolism is higher for third- and fourth-generation combined oral contraceptives than for first- and second-generation combined oral contraceptives.
The use and adverse reactions of combined oral contraceptives in Croatia
The Agency for Medicinal Products and Medical Devices (HALMED) is actively monitoring all new information about the use of combined oral contraceptives and will act to PRAC recommendations, accordingly. There are no new signals of an increased incidence of venous thromboembolism events for combined oral contraceptives. The adverse reactions reported to HALMED do not differ from earlier known risks for those medicines. All known data about the risk of venous thromboembolism associated with the use of combined oral contraceptives are listed in Summaries of Product Characteristics and are regularly updated. HALMED is continuously working on raising awareness of the risk of venous thromboembolism associated with the use of combined oral contraceptives and in 2008 a Dear Health Care Professional letter (in Croatian) thereof was sent. The letter says which patients may use those medicines and what is the risk of venous thromboembolism, as well as what are the early symptoms that health care professionals should warn patients about in order for the venous thromboembolism to be promptly recognised. Taking into account that the risk of venous thromboembolism is higher for third- and fourth-generation, in July 2011 HALMED published recommendations thereof to health care professionals that are still in effect and that you may view here (in Croatian).
The consumption of oral contraceptives in the Republic of Croatia from 2007 to 2011
The consumption of combined oral contraceptives in the Republic of Croatia was stable in the period 2007-2011 for all classes of those medicines, except for medicines containing a drospirenon and estrogen combination (fourth-generation oral contraceptives), as shown here. There is a significant decrease in the last years of the consumption of the aforementioned combination, which is in compliance with the current recommendations about the risk of venous thromboembolism that carry "newer" contraceptives which indicates that Croatian doctors recognise the risks of the use of those medicines.
Information about the medicinal product Diane-35 coated tablets
On 30th January 2013, the French Agency for the Safety of Health Products (ANSM) published on its website that a marketing authorisation suspension procedure for the medicinal product Diane-35 in France has been initiated that will be completed in the next three months. The aforementioned medicine is authorised in France for acne treatment in women. However, ANSM concluded that the benefits risks ratio of the use of this medicines for the aforementioned indication is negative due to a possibility of thromboembolism.
The medicinal product Diane-35 coated tablets is authorised in Croatia for androgenisation symptom treatment as well as acne treatment caused by this hormonal disorder in women. The androgenisation in women means an occurrence of masculine secondary sex characteristics like hirsutism or androgenic alopecia. The androgenisation in women often occurs within the syndrome of polycystic ovaries, accompanied by an ovulation disorder. The syndrome of polycystic ovaries is often associated with numerous other disorders in the body, which includes an increased predisposition to blood coagulation and forming of blood clots.
We emphasise that the medicinal product Diane-35 coated tablets is not authorised for use as an oral contraceptive, but exclusively for androgenisation syndrome treatment in women that generally occurs within the syndrome of polycystic ovaries. From the above mentioned it is evident that the authorised indication in the Republic of Croatia is different from that authorised in France.
From 2007 until now we received totally seven reports to thromboembolism events with the use of Diane-35 coated tablets. This number of reports is expected and it is in accordance with the reporting rate of thromboembolic adverse reactions for the above mentioned medicine elsewhere in the world. In three reports out of seven, there was a case of venous thrombosis (blood clots in veins), in other three there was a lungs embolism (a thrombosis of lungs vessels by clots transported via circulation from veins), whereas in one case there was an arterial thrombosis (a blood clot in artery). In all seven cases, the patients recovered entirely from the thromboembolism.
HALMED will keep the use of the medicinal product Diane-35 under close monitoring and will inform the public promptly about any new information.
Conclusion
There is no need for stopping the use of these medicines till further notice, in patients taking any combined oral contraceptive or medicines containing female sex hormones. For every further question about the treatment, one should ask her doctor. We remind health care professionals that indications, contraindications, warnings and other caution measures specified in the Summary of Product Characteristics that are available in the Medicinal Products/Medicinal Products Database section of HALMED’s webpages or here, should be taken into account, when prescribing those medicines.
When taking decisions on eventual regulatory actions linked to risks from venous thromboembolism associated with the use of third- and fourth-generation oral contraceptives, as well as other medicines containing female sex hormones (including the medicinal product Diane-35 coated tablets), HALMED will follow recommendations of the European Medicines Agency, which means its Pharmacovigilance and Risk Assessment Committee (PRAC), in whose work HALMED participates as an active observer.
HALMED will continue to monitor the safe use of third- and fourth-generation combined oral contraceptives, as well as other medicines containing female sex hormones and will inform the public promptly about any new information.
