Safety Alerts

Update on risk of thromboembolism associated with combined hormonal contraceptives

29 August 2014

Audiences

Healthcare professional

Industry member

Product-type

Therapeutic Products

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HSA would like to update healthcare professionals on the outcome of its review on the risk of thromboembolism associated with combined hormonal contraceptives (CHCs). Although venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism, is a known potential risk with the use of CHCs, current evidence showed that the small absolute risk of VTE associated with CHCs may differ depending on the type of progesterone present in the preparation. CHCs are also associated with an increased risk of arterial thromboembolism (ATE) but there is insufficient evidence to demonstrate if the ATE risk varies between different CHCs.

Relative risks of CHCs

HSA’s review focused on the ‘third- and fourth-generation’ CHCs, which have been registered in Singapore since 1990. These CHCs contain newer progesterones at lower doses as compared to the ‘first- and second-generation’ CHCs (e.g., those containing norethisterone and levonorgestrel, respectively), thus resulting in fewer adverse effects such as weight gain, fluid retention, and headaches. The progesterone contained in the ‘third- and fourth-generation’ CHCs includes desogestrel, dienogest, drospirenone, etonogestrel, gestodene, nomegestrol, norelgestromin or norgestimate, which are combined with varying doses of ethinylestradiol or estradiol. There are 11 brands of these CHCs registered locally in various formulations such as oral tablet, transdermal patch or vaginal ring (Table 1).

Table 1. ‘Third- and fourth-generation’ CHCs registered locally

Table caption

Active ingredients	Brand name
Desogestrel/Ethinylestradiol	Gracial®, Marvelon®, Mercilon®
Dienogest/Estradiol	Qlaria®
Drospirenone/Ethinylestradiol	Yasmin®, Yaz®
Etonogestrel/Ethinylestradiol	Nuvaring® vaginal ring
Gestodene/Ethinylestradiol	Gynera®, Meliane®
Nomegestrol/Estradiol	Zoely®
Norelgestromin/Ethinylestradiol	Evra® transdermal patch
Norgestimate/Ethinylestradiol	Not registered locally

Based on scientific evidence to date, CHCs containing levonorgestrel, norethisterone and norgestimate have the lowest VTE risk. Estimates of the relative risk of VTE with different generations of CHCs compared with that for levonorgestrel-containing CHC (a ‘second-generation’ CHC) are provided in Table 2.¹

Table 2. Risk of VTE with CHCs

Table caption

Progesterone in CHC	Relative risk versus levonorgestrel-containing CHC	Estimated incidence (per 10,000 women-years)
Non-pregnant non-user	–	2
Levonorgestrel	Reference	5–7
Norgestimate, Norethisterone*	1.0	5–7
Desogestrel, rospirenone, Gestodene	1.5–2.0	9–12
Etonogestrel, Norelgestromin	1.0–2.0	6–12
Dienogest, Nomegestrel	Not yet established. Further studies are ongoing or planned for data collection	Not yet established. Further studies are ongoing or planned for data cllection

* There are no CHCs containing norgestimate or norethisterone registered in Singapore.

The risk of ATE (myocardial infarction, cerebrovascular accident) is also known to be increased with the use of CHCs. In a large historical cohort study by Lidegaard et al, the relative risks for ischaemic stroke and myocardial infarction in users of CHCs versus non-users were 1.5–2.2 and 1.7–2.3, respectively.² However, there is insufficient evidence to demonstrate any difference in ATE risk between CHCs.

International regulatory actions

The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee completed its safety assessment in January 2014, which concluded that the benefit-risk balance of the reviewed products in the indication of contraception remains favourable.¹ The Committee recommended placing emphasis on the importance of an individual woman’s risk factors and the need to assess them regularly, as well as raising awareness of the signs and symptoms of VTE and ATE which should be described to women when a CHC is prescribed.

HSA’s advisory and actions

Healthcare professionals should take into consideration the latest evidence on the risk of thromboembolism associated with CHCs when discussing the most suitable type of contraceptive for their patient. Careful consideration should be given to the woman’s risk factors for thromboembolism and these risk factors should be reassessed regularly. The risk of thromboembolism with a CHC is higher during the first year of use, and when re-initiating its use after a break of four or more weeks.

HSA is working with the companies to update the local package inserts of ‘third- and fourth-generation’ CHCs to reflect the current available information, including strengthening the contraindications for use, highlighting the difference in VTE risk of each product versus a levonorgestrel-containing CHC, and updating the baseline VTE rates. A Dear Healthcare Professional Letter was issued on 26 May 2014 to update healthcare professionals on HSA’s review outcome.³