Qlaira (Estradiol valerate/dienogest)

A Phase IV, prospective, multicenter, noninterventional, observational study in 3,152 women (aged 18–50 years) switching from an EE-containing OC pill to the E2V/DNG pill or a POP. The study was conducted at 375 investigational sites in eleven countries: the Czech Republic, France, Germany, Greece, Hungary, Israel, Italy, the Russian Federation, Slovakia, Sweden, and the UK.

For inclusion, women must have been using EE-containing OCs for ≥3 months prior to enrollment and must have decided to switch either to the E2V/DNG pill or to a POP, depending on individual choice. Exclusion criteria were in accordance with the contraindications, precautions, and warnings for women receiving the E2V/DNG pill or chosen POP based on the approved product labeling in each country. Women who were breastfeeding were also excluded.

The E2V/DNG pill was administered via a dynamic dosing regimen (E2V 3 mg on days 1 and 2, E2V 2 mg/DNG 2 mg on days 3–7, E2V 2 mg/DNG 3 mg on days 8–24, E2V 1 mg on days 25–26, and placebo on days 27–28). The chosen POP was administered according to the relevant prescribing information. As this is a noninterventional study, the duration of treatment was at the discretion of the physician. Women were followed for 1 year.

Adapted from: Briggs P et al. Int J Womens Health 2016;8:477–487.

A Phase IV, prospective, multicenter, noninterventional, observational study in 3,152 women (aged 18–50 years) switching from an EE-containing OC pill to the E2V/DNG pill or a POP. The study was conducted at 375 investigational sites in eleven countries: the Czech Republic, France, Germany, Greece, Hungary, Israel, Italy, the Russian Federation, Slovakia, Sweden, and the UK.

For inclusion, women must have been using EE-containing OCs for ≥3 months prior to enrollment and must have decided to switch either to the E2V/DNG pill or to a POP, depending on individual choice. Exclusion criteria were in accordance with the contraindications, precautions, and warnings for women receiving the E2V/DNG pill or chosen POP based on the approved product labeling in each country. Women who were breastfeeding were also excluded.

The E2V/DNG pill was administered via a dynamic dosing regimen (E2V 3 mg on days 1 and 2, E2V 2 mg/DNG 2 mg on days 3–7, E2V 2 mg/DNG 3 mg on days 8–24, E2V 1 mg on days 25–26, and placebo on days 27–28). The chosen POP was administered according to the relevant prescribing information. As this is a noninterventional study, the duration of treatment was at the discretion of the physician. Women were followed for 1 year.

Adapted from: Briggs P et al. Int J Womens Health 2016;8:477–487.

Qlaira^® (estradiol valerate/dienogest) is a combined oral contraceptive pill that is licensed for the treatment of menorrhagia in women without organic pathology who desire oral contraception or birth control.

Qlaira^® may benefit patients who desire a less invasive option for patients who experience heavy menstrual bleeding but are reluctant to have the first-line treatment of a levonorgestrel intrauterine system, for example Mirena^® (52mg intrauterine delivery system levonorgestrel), fitted. Qlaira^® can affect a woman’s menstrual cycle and reduce heavy periods. Women taking the combined oral contraceptive may experience amenorrhoea despite not being pregnant. Based on patient diaries, amenorrhoea occurs in approximately 15% of cycles. For more information on side effects of Qlaira^®, click here.

As 42% of missed pills occur in the first week after restarting a new pack, this indicates it may be difficult for women to remember the day to start a new pack after a 7-day break (the 42% of missed pills is not specific to Qlaira^®).

Qlaira^® includes 26 hormone pills and two non-hormone, placebo inactive tablets as a 28-day regimen (with no intake break), which is likely to have higher compliance rates than other regimens which include an intake break..

While the dosing of Qlaira^® (estradiol valerate/dienogest) is different from that of other combined oral contraceptives (with the pill colours relating to different dosages and active ingredients), this does not change the routine of taking 1 pill per day.

Qlaira^® should be taken at about the same time every day for 28 consecutive days, following the direction of the arrows on the wallet.
Each subsequent wallet is started the day after the last tablet of the previous wallet (no intake break).

Each packet contains 28 film-coated tablets; 26 hormone pills and 2 non-hormone pills; in the following order:

• 2 dark yellow tablets each containing 3 mg estradiol valerate
• 5 medium red tablets each containing 2 mg estradiol valerate and 2 mg dienogest
• 17 light yellow tablets each containing 2 mg estradiol valerate and 3 mg dienogest
• 2 dark red tablets each containing 1 mg estradiol valerate
• 2 white tablets that do not contain active substances

For information about what a patient should do in the case of missing a pill, click here.

Ensure the patient informs you of all the medicines or herbal products they are using as some can:

• Have an influence on the pharmacokinetics and pharmacodynamics of Qlaira^® (estradiol valerate/dienogest)
• Make it less effective in preventing pregnancy with possible contraceptive failure
• Cause unexpected breakthrough bleeding

These include:

• Medicines used for the treatment of:
  • Epilepsy (e.g. primidone, phenytoin, barbiturates, carbamazepine, oxcarbazepine, topiramate)
  • Tuberculosis (e.g. rifampicin)
  • HIV and Hepatitis C virus infections (so-called protease inhibitors and non-nucleoside reverse transcriptase inhibitors such as ritonavir, nevirapine, efavirenz)
  • Fungal infections (e.g. griseofulvin, ketoconazole)
• The herbal remedy St John’s wort
• Qlaira^® may influence the effect of other medicines, for example:
  • medicines containing cyclosporine
  • the anti-epileptic lamotrigine (this could lead to an increased frequency of seizures)

Refer to the Summary of Product Characteristics and Patient information leaflet (available in references) for further interaction data and additional specific guidance on when barrier methods should be used.

The most commonly reported side effects with Qlaira^® (estradiol valerate/dienogest) when used as an oral contraceptive or in the treatment of menorrhagia in women without organic pathology who desire oral contraception are acne, breast discomfort, headache, intracyclic bleeding, nausea and weight gain.

Patients can be reassured that intracyclic bleeding should decline after the first few months of use.

There is an increased risk of venous thromboembolism (VTE) or arterial thromboembolism (ATE) for all patients taking combined hormonal contraceptives.

Epidemiological studies in women who use low-dose (<50 µg ethinylestradiol) combined hormonal contraceptives (CHCs) have found that out of 10,000 women, between about 6 and 12 will develop a VTE in one year. It is estimated that out of 10,000 women who use a levonorgestrel-containing CHC about 6 will develop a VTE in 1 year.

Limited epidemiological evidence suggests that the risk of VTE with the use of Qlaira^® may be in the same range as the risk with other CHCs including CHCs containing levonorgestrel.

Some women using hormonal contraceptive pills including Qlaira^® have reported depression or depressed mood. Depression can be serious and may sometimes lead to suicidal thoughts. Women should be advised to contact their physician in case of mood changes and depressive symptoms, including shortly after initiating the treatment. Depression and mood change such as mood swings are uncommon, around 0.1–1% may be affected.

An increased risk of VTE or ATE is present for all women taking combined hormonal contraceptives. Harmful blood clots are rare, between 0.01–0.1% of women may be affected. The existence of other conditions/factors such as age, smoking and being overweight may increase the risk of having a blood clot.

For full guidance refer to the Summary of Product Characteristics.

The Patient Information Leaflet can be downloaded here.

There are a number of steps you can take to help minimise the risk of complications (such as thromboembolism) for patients when prescribing combined hormonal contraceptives. These include assessing:

• Age: particularly above 35 years
• Smoking: women should be advised not to smoke if they wish to use a combined hormonal contraceptive. Women over 35 who continue to smoke should be strongly advised to use a different method of contraception
• Hypertension
• Obesity (body mass index [BMI] over 30 kg/m²): Risk increases substantially as BMI increases. This is particularly important in women with additional risk factors
• Positive family history: if a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any combined hormonal contraceptive use
• Migraine: an increase in frequency or severity of migraine during use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation
• Prolonged immobilisation, major surgery, any surgery to the legs or pelvis, neurosurgery or major trauma: Note: temporary immobilisation including air travel >4 hours can also be a risk factor for VTE, particularly in women with other risk factors.
• Other medical conditions associated with VTE: for example, cancer, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn's disease or Ulcerative Colitis) and sickle cell disease.
• Other medical conditions associated with ATE: Diabetes mellitus, hyperhomocysteinaemia, valvular heart disease and atrial fibrillation, dyslipoproteinaemia and systemic lupus erythematosus.

Refer to the Qlaira^® summary of product characteristics for detailed information including the latest evidence and a consultation checklist for prescribers.

Between 1–10% of women who take Qlaira^® (estradiol valerate/dienogest) reported weight gain.

Weight gain is one of the most commonly reported adverse reactions with Qlaira^® when used as an oral contraceptive or in the treatment of menorrhagia in women without organic pathology who desire oral contraception.

Women should be advised to contact their physician if they gain a lot of weight.

Qlaira^® (estradiol valerate/dienogest) is a treatment of menorrhagia in women without organic pathology who desire oral contraception.

Expected bleeding

Withdrawal bleeding usually starts during the intake of the last tablets of a wallet and may not have finished before the next wallet is started. In some women, the bleeding starts after the first tablets of the new wallet are taken.

If expected bleeding does not occur twice in a row, patients should contact a doctor to rule out pregnancy. Pregnancy must be ruled out before Qlaira use is continued.

Women taking the Qlaira^® pill may experience amenorrhoea despite not being pregnant. Based on patient diaries, amenorrhoea occurs in approximately 15% of cycles.

Intracyclic bleeding

During the first few months of taking Qlaira^®, patients may have unexpected bleeding. Usually bleeding starts on Day 26 (the day they take the second dark red tablet) or the following day(s).

The information provided by patients in the diaries they kept during a clinical study of Qlaira^® shows that it is not unusual to experience unexpected bleeding in a given cycle (10–18% of users). If unexpected bleeding occurs more than 3 months in a row, or if it begins after some months, refer to the Summary of Product Characteristics for guidance.

Qlaira^® (estradiol valerate/dienogest) is a form of contraception that prevents pregnancy and has demonstrated reliable contraceptive efficacy in women aged 18–50 years with an adjusted Pearl Index of 0.42. Note that no form of contraception is 100% effective.

If patients are more than 12 hours late taking a tablet, the protection against pregnancy may be reduced. Depending on the day of the cycle on which one tablet has been missed, advise the patient to take additional contraceptive precautions, e.g. a barrier method such as a condom.

Likewise, in cases of severe gastrointestinal disturbances (e.g. vomiting or diarrhoea), absorption may not be complete and additional contraceptive measures should be taken.

To assist patients the missed pill rules are printed directly onto the Qlaira^® (estradiol valerate/dienogest) cycle pack. Patients must be informed that the missed pill rules are different to those for other contraceptive pill regimens.

If the woman is less than 12 hours late in taking any tablet, contraceptive protection is not reduced. The woman should take the tablet as soon as she remembers and should take further tablets at the usual time.

If she is more than 12 hours late in taking any tablet, contraceptive protection may be reduced. The woman should take the last missed Qlaira^® pill as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time.

Depending on the day of the cycle on which the tablet has been missed (see chart above for details), backup contraceptive measure (e.g. a barrier method such as a condom) have to be used to help prevent pregnancy according to the following principles:

If a woman has forgotten to start the next packet, or if she has missed one or more tablets during Days 3–9 of the wallet, she may already be pregnant (provided she has had intercourse in the 7 days before the oversight). The more tablets (of those with the two combined active ingredients on Days 3–24) that are missed and the closer they are to the placebo tablet phase, the higher the risk of a pregnancy.

If the woman missed Qlaira^® pills and subsequently has no withdrawal bleed at the end of the wallet/beginning of new wallet, the possibility of a pregnancy should be considered.

Alternative hormonal contraceptives that offer a pill-free method of contraception include Kyleena^® (19.5mg intrauterine delivery system levonorgestrel) and Mirena^® (52mg intrauterine system levonorgestrel).

The Patient Information Leaflet can be downloaded here.