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Health professionals are advised that the Product Information (PI) documents for combined oral contraceptives containing dienogest have been updated to include more detailed information on the risk of venous thromboembolism. This is an update of a previous MSU article in December 2016 on combined hormonal contraceptives and risk of venous and arterial thromboembolism.
Dienogest, a progestogen, is available in two combined oral contraceptives (COCs) in Australia. These are marketed by Bayer under the brand names Valette and Qlaira:
- Valette (dienogest/ethinylestradiol) is indicated for oral contraception and treatment of mild-moderate acne in women wanting contraception
- Qlaira (dienogest/estradiol valerate) is indicated for oral contraception and treatment of heavy or prolonged menstrual bleeding in women wanting contraception (with no organic pathology).
Why have warnings about VTE risk been updated?
A review by the TGA in 2016 found that while the risk of venous thromboembolism (VTE), such as deep vein thrombosis and pulmonary embolism, is generally rare and occurs in approximately 2 in 10,000 women, the risk is slightly increased in women using a COC containing ethinylestradiol and a progestogen. However, the degree of risk varies depending on the progestogen (see Table in the 2016 MSU article). At the time of the 2016 review, the risk of developing VTE from a combined oral contraceptive containing dienogest was listed as 'not yet known'.
Since 2016, the sponsor for both Valette and Qlaira conducted a meta-analysis of four prospective cohort studies investigating the VTE risk associated with short- and long-term use of contraceptives containing dienogest/ethinylestradiol and levonorgestrel/ethinylestradiol. The sponsor also reviewed epidemiological studies which described variable risk estimates for VTE with dienogest/ethinylestradiol and levonorgestrel/ethinylestradiol.
The risk of VTE in women taking dienogest/ethinylestradiol was estimated to be 8–11/10,000 in a year compared to 5–7/10,000 for women taking levonorgestrel/ethinylestradiol (see Table below).
Approximate risk of developing a VTE in a year, per 10,000 women
| Progestogen component of COC in combination with ethinylestradiol | Risk |
|---|---|
| levonorgestrel, norethisterone, norgestimate | 5-7 |
| etonogestrel, norelgestromin | 6-12 |
| drospirenone, gestodene, desogestrel, cyproterone* | 9-12 |
| dienogest | 8-11 |
| chlormadinone, nomegestrol | Not yet known |
* While cyproterone is indicated for the treatment of moderate to severe acne related to androgen sensitivity and/or hirsutism, it is known to have efficacy as a contraceptive. The risk of developing a blood clot associated with cyproterone use is considered to be 1.5 to 2 times higher than for CHCs containing levonorgestrel and may be similar to the risk with contraceptives containing gestodene, desogestrel or drospirenone.
As a result of these analyses on VTE, the sponsor has included additional detail in the PI for dienogest/ethinylestradiol (Valette):
'Epidemiological studies, that compared the risk of VTE associated with use of dienogest/ethinylestradiol to the risk with use of COCs containing levonorgestrel/ethinylestradiol reported differing results ranging from no difference in risk to a three-fold increase in risk.'
'Meta-analysis of four large prospective cohort studies yielded an adjusted Hazard Ratio of 1.57 (95% Confidence Interval, 1.07-2.30) for VTE risk with Valette compared to COCs containing levonorgestrel/30µg ethinylestradiol. These studies cover 38,708 women –years of exposure to Valette.'
Similar warnings about the risk of VTE have also been added to Product Information in Europe based on a recommendation from the European Medicines Agency.
A specific and robust study to address the risk of VTE with the use of estradiol valerate (Qlaira) has been conducted. The INAS-SCORE study showed that Qlaira was associated with a similar or even lower risk of VTE compared to LNG-containing COCs or other COCs.[1]
What this means for health professionals
In women who have been using a dienogest-containing contraceptive without a problem, there is no reason to stop taking it based on this updated information. However, it is important that women are aware of the risk of VTE and its signs and symptoms such as pain or swelling in the legs, sudden unexplained breathlessness, rapid breathing or cough, and chest pain.
It is important to know the contraindications when prescribing oral contraceptives and consider a woman's individual risk factors for thromboembolism, including smoking, obesity, increasing age, migraines and a family history of VTE.
For more detail about prescribing, see the latest PI documents for dienogest/ethinylestradiol and dienogest/estradiol valerate.
Reference
| [1] | Dinger J, Do Minh T, Heinemann K. Impact of estrogen type on cardiovascular safety of combined oral contraceptives. Contraception 2016; 94:328-339 |
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What to report? You don't need to be certain, just suspicious!
The TGA encourages the reporting of all suspected adverse reactions to medicines, including vaccines, over-the-counter medicines, herbal, traditional or alternative remedies.
We particularly request reports of:
- all suspected reactions to new medicines (look for the Black Triangle in PI and CMI documents - this symbol identifies medicines that are new or being used differently)
- all suspected medicines interactions
- suspected reactions causing death, admission to hospital or prolongation of hospitalisation, increased investigations or treatment, or birth defects.
Reports may be submitted:
- online at www.tga.gov.au
- by fax to 02 6232 8392
- by email to ADR.Reports@tga.gov.au
For more information about reporting, visit www.tga.gov.au or contact the TGA's Pharmacovigilance and Special Access Branch ADR.Reports@tga.gov.au.
Disclaimer
Medicines Safety Update is aimed at health professionals. It is intended to provide practical information to health professionals on medicine safety, including emerging safety issues. The information in Medicines Safety Update is necessarily general and is not intended to be a substitute for a health professional's judgment in each case, taking into account the individual circumstances of their patients. Reasonable care has been taken to ensure that the information is accurate and complete at the time of publication. The Australian Government gives no warranty that the information in this document is accurate or complete, and shall not be liable for any loss whatsoever due to negligence or otherwise arising from the use of or reliance on this document.
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Medicines Safety Update is written by staff from the Pharmacovigilance and Special Access Branch.
Acting Editor: Dr Catherine Brogan
Deputy Editor: Mr Michael Pittman
Contributor: Dr Nicola Murphy and Dr Fiona Mackinnon