Warnings
If any of the conditions or risk factors mentioned below is present, the suitability of Drovelis should be discussed with the woman before she decides to start using Drovelis.
In the event of aggravation, or first appearance of any of these conditions or risk factors, the woman should be advised to contact her doctor to determine whether the use of Drovelis should be discontinued. All data presented below are based upon epidemiological data obtained with CHCs containing ethinylestradiol. Drovelis contains estetrol. As no epidemiological data are yet available with estetrol containing-CHCs, the warnings are considered applicable to the use of Drovelis.
In case of suspected or confirmed VTE or ATE, CHC use must be discontinued. In case anticoagulant therapy is started, adequate alternative non-hormonal contraception should be initiated because of the teratogenicity of anticoagulant therapy (coumarins).
Circulatory disorders
Risk of VTE
The use of any CHC increases the risk of VTE compared with no use. Products that contain low dose ethinylestradiol (<50 µg ethinylestradiol) combined with levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. It is not yet known how the risk with Drovelis compares with these lower risk products. The decision to use any product other than one known to have the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with CHCs, how her current risk factors influence this risk, and that her VTE risk is highest in the first ever year of use.
There is also some evidence that the risk is increased when a CHC is re-started after a break in use of 4 weeks or more.
In women who do not use a CHC and are not pregnant about 2 out of 10,000 will develop a VTE over the period of one year. However, in any individual woman the risk may be far higher, depending on her underlying risk factors (see below).
Epidemiological studies in women who use low dose (<50 µg ethinylestradiol) combined hormonal contraceptives have found that out of 10,000 women between about 6 and 12 will develop a VTE in one year.
It is estimated1 that out of 10,000 women who use a CHC containing ethinylestradiol and drospirenone, between 9 and 12 women will develop a VTE in one year; this compares with about 62 in 10,000 women who use a levonorgestrel-containing CHC.
It is not yet known how the risk of VTE with CHC containing estetrol and drospirenone compares with the risk with low dose levonorgestrel-containing CHCs.
The number of VTEs per year with low-dose CHCs is fewer than the number expected in women during pregnancy or in the postpartum period.
VTE may be fatal in 1-2% of cases.
Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, e.g., hepatic, mesenteric, renal or retinal veins and arteries.
Risk factors for VTE
The risk for venous thromboembolic complications in CHC users may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see table 1).
Drovelis is contraindicated if a woman has multiple risk factors that put her at high risk of venous thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors – in this case her total risk of VTE should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed (see section 4.3).
Table 1: Risk factors for VTE
| Risk factor | Comment |
| Obesity (body mass index [BMI] over 30 kg/m2). | Risk increases substantially as BMI rises. Particularly important to consider if other risk factors also present. |
| 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. | In these situations, it is advisable to discontinue use of the pill (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation. Another method of contraception should be used to avoid unintentional pregnancy. Antithrombotic treatment should be considered if Drovelis has not been discontinued in advance. |
| Positive family history (VTE ever in a sibling or parent especially at a relatively early age, e.g., before 50 years). | If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use. |
| Other medical conditions associated with VTE. | Cancer, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell disease. |
| Increasing age. | Particularly above 35 years. |
There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in the onset or progression of venous thrombosis.
The increased risk of thromboembolism in pregnancy, and particularly the 6-week period of the puerperium, must be considered (for information on pregnancy and lactation see section 4.6).
Symptoms of VTE (DVT and PE)
In the event of symptoms, women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.
Symptoms of DVT can include:
- unilateral swelling of the leg and/or foot or along a vein in the leg;
- pain or tenderness in the leg which may be felt only when standing or walking;
- increased warmth in the affected leg; red or discoloured skin on the leg.
Symptoms of PE can include:
- sudden onset of unexplained shortness of breath or rapid breathing;
- sudden coughing which may be associated with haemoptysis;
- sharp chest pain;
- severe light headedness or dizziness;
- rapid or irregular heartbeat.
Some of these symptoms (e.g., 'shortness of breath', 'coughing') are non-specific and might be misinterpreted as more common or less severe events (e.g., respiratory tract infections).
Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of an extremity.
If the occlusion occurs in the eye symptoms can range from painless blurring of vision which can progress to loss of vision. Sometimes loss of vision can occur almost immediately.
Risk of ATE
Epidemiological studies have associated the use of CHCs with an increased risk for arterial thromboembolism (myocardial infarction [MI]) or for cerebrovascular accident (e.g., TIA, stroke). Arterial thromboembolic events may be fatal.
Risk factors for ATE
The risk of arterial thromboembolic complications or of a cerebrovascular accident in CHC users increases in women with risk factors (see table 2). Drovelis is contraindicated if a woman has one serious or multiple risk factors for ATE that puts her at high risk of arterial thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors – in this case her total risk should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed (see section 4.3).
Table 2: Risk factors for ATE
| Risk factor | Comment |
| Increasing age. | Particularly above 35 years. |
| Smoking. | Women should be advised not to smoke if they wish to use a CHC. Women over 35 years who continue to smoke should be strongly advised to use a different method of contraception. |
| Hypertension. | |
| Obesity (BMI over 30 kg/m2). | Risk increases substantially as BMI increases. Particularly important in women with additional risk factors. |
| Positive family history (arterial thromboembolism ever in a sibling or parent especially at relatively early age, e.g., below 50 years). | If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use. |
| Migraine. | An increase in frequency or severity of migraine during CHC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation. |
| Other medical conditions associated with adverse vascular events. | Diabetes mellitus, hyperhomocysteinaemia, valvular heart disease and atrial fibrillation, dyslipoproteinaemia and systemic lupus erythematosus. |
Symptoms of ATE
In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.
Symptoms of a cerebrovascular accident can include:
- sudden numbness or weakness of the face, arm or leg, especially on one side of the body;
- sudden trouble walking, dizziness, loss of balance or coordination;
- sudden confusion, trouble speaking or understanding;
- sudden trouble seeing in one or both eyes;
- sudden, severe or prolonged headache with no known cause;
- loss of consciousness or fainting with or without seizure.
Temporary symptoms suggest the event is a transient ischaemic attack (TIA).
Symptoms of myocardial infarction (MI) can include:
- pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone;
- discomfort radiating to the back, jaw, throat, arm, stomach;
- feeling of being full, having indigestion or choking;
- sweating, nausea, vomiting or dizziness;
- extreme weakness, anxiety, or shortness of breath;
- rapid or irregular heartbeats.
Tumours
An increased risk of cervical cancer in long-term users of CHCs containing ethinylestradiol (>5 years) has been reported in some epidemiological studies, but there continues to be controversy about the extent to which this finding is attributable to the confounding effects of sexual behaviour and other factors such as human papilloma virus (HPV).
With the use of the higher-dosed CHCs (50 µg ethinylestradiol) the risk of endometrial and ovarian cancer is reduced. Whether this also applies to estetrol-containing CHCs remains to be confirmed.
A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR=1.24) of having breast cancer diagnosed in women who are currently using CHCs containing ethinylestradiol. The excess risk gradually disappears during the course of the 10 years after cessation of CHC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent CHC users is small in relation to the overall risk of breast cancer. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in CHC users, the biological effects of CHCs or a combination of both.
In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been reported in users of CHCs containing ethinylestradiol. In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhages. Therefore, a hepatic tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage occur in women taking CHCs.
Hepatitis C
During clinical studies with patients treated for hepatitis C virus (HCV) infection with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, ALT elevations higher than 5 times the upper limit of normal occurred significantly more frequently in women using ethinylestradiol-containing medicinal products such as CHCs. Additionally, also in patients treated with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co-administration with the combination therapeutic regimen ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin and also the regimen glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir. See also section 4.5.
Other conditions
The progestogen component in Drovelis, drospirenone, is an aldosterone antagonist with potassium sparing properties. In most cases, no increase of potassium levels would be expected. In a clinical study with drospirenone, however, in some patients with mild or moderate renal impairment and concomitant use of potassium-sparing medicinal products, serum potassium levels increased slightly, but not significantly, during intake of 3 mg drospirenone for 14 days. Therefore, it is recommended to check serum potassium during the first treatment cycle with Drovelis in patients presenting with renal insufficiency and a pretreatment serum potassium in the upper reference range, and particularly during concomitant use of potassium sparing medicinal products. See also section 4.5.
Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when using CHCs.
Although small increases in blood pressure have been reported in many women taking CHCs, clinically relevant increases are rare. A relationship between CHC use and clinical hypertension has not been established. However, if a sustained clinically significant hypertension develops during the use of a CHC, then it is prudent for the physician to suspend the intake of the tablets and treat the hypertension. Where considered appropriate, CHC use may be resumed if normotensive values can be achieved with antihypertensive therapy.
The following conditions have been reported to occur or deteriorate with both pregnancy and CHC use, but the evidence of an association with CHC use is inconclusive: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham's chorea; herpes gestationis; otosclerosis-related hearing loss.
Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.
Acute or chronic disturbances of liver function may necessitate the discontinuation of CHC use until markers of liver function return to normal. Recurrence of cholestatic jaundice which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of CHCs.
Although CHCs may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics using low-dose CHCs (containing <50 µg ethinylestradiol). However, diabetic women should be carefully observed, particularly in the early stage of CHC use.
Worsening of endogenous depression, of epilepsy, of Crohn's disease and ulcerative colitis has been reported during CHC use.
Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use (see section 4.8). Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their physician in case of mood changes and depressive symptoms, including shortly after initiating the treatment.
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking CHCs.
Medical examination/consultation
Prior to the initiation or reinstitution of Drovelis a complete medical history (including family history) should be taken and pregnancy must be ruled out. Blood pressure should be measured and a physical examination should be performed, guided by the contraindications (see section 4.3) and warnings (see section 4.4). It is important to draw a woman's attention to the information on venous and arterial thrombosis, including the risk of Drovelis compared with other CHCs, the symptoms of VTE and ATE, the known risk factors and what to do in the event of a suspected thrombosis. The woman should also be instructed to carefully read the user leaflet and to adhere to the advice given. The frequency and nature of examinations should be based on established practice guidelines and be adapted to the individual woman.
Women should be advised that hormonal contraceptives do not protect against human immunodeficiency virus (HIV) infection and/or acquired immunodeficiency syndrome (AIDS) and other sexually transmitted diseases.
Reduced efficacy
The efficacy of CHCs may be reduced in the event of missed tablets (see section 4.2), gastro-intestinal disturbances during pink active tablet taking (see section 4.2) or concomitant medicinal products (see section 4.5).
Cycle control
With all CHCs, unscheduled bleeding (spotting or bleeding) may occur, especially during the first months of use. Therefore, the evaluation of any irregular bleeding is only meaningful after an adaptation interval of about three cycles. Unscheduled bleeding or spotting occurred in 14% to 20% of women using Drovelis. Most of these episodes concerned spotting only.
If bleeding irregularities persist or occur after previously regular cycles, then non-hormonal causes should be considered, and adequate diagnostic measures are indicated to exclude malignancy or pregnancy. These may include curettage.
In a small percentage of women (6-8%), withdrawal bleeding may not occur during the placebo tablet phase. If absence of withdrawal bleeding occurs and Drovelis has been taken according to the instructions as described in section 4.2, pregnancy is unlikely. However, pregnancy must be ruled out before Drovelis use is continued, if Drovelis has not been taken as directed, or if two consecutive withdrawal bleeds do not occur.
Laboratory tests
The use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins, e.g., corticosteroid binding globulin (CBG) and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range. Drospirenone causes an increase in plasma renin activity and plasma aldosterone induced by its mild anti-mineralocorticoid activity.
Excipients
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.
1 These incidences were estimated from the totality of the epidemiological study data, using relative risks for the different products compared with levonorgestrel-containing CHCs.
2 Mid-point of range of 5-7 per 10,000 WY, based on a relative risk for CHCs containing levonorgestrel versus non-use of approximately 2.3 to 3.6
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This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
