Leaflet DROVELIS 3mg / 14.2mg film-coated tablets

If any of the conditions or risk factors mentioned below is present, the suitability of Drovelis should bediscussed with the woman before she decides to start using it.

In the event of aggravation, or first appearance of any of these conditions or risk factors, the womanshould be advised to contact her doctor to determine whether the use of Drovelis should bediscontinued. All data presented below are based upon epidemiological data obtained with CHCscontaining ethinylestradiol. It contains estetrol. As no epidemiological data are yet available withestetrol 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 anticoagulanttherapy is started, adequate alternative non-hormonal contraception should be initiated because of theteratogenicity 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 doseethinylestradiol (< 50 mcg ethinylestradiol) combined with levonorgestrel, norgestimate ornorethisterone 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 thanone known to have the lowest VTE risk should be taken only after a discussion with the womanto ensure she understands the risk of VTE with CHCs, how her current risk factors influencethis 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 useof 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 overthe period of one year. However, in any individual woman the risk may be far higher, depending on herunderlying risk factors (see below).

Epidemiological studies in women who use low dose (< 50 mcg ethinylestradiol) combined hormonalcontraceptives have found that out of 10 000 women between about 6 and 12 will develop a VTE in oneyear.

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 womenwho use a levonorgestrel-containing CHC.

It is not yet known how the risk of VTE with CHC containing estetrol and drospirenone compareswith 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 duringpregnancy 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 awoman 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 venousthrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increasein risk is greater than the sum of the individual factors - in this case her total risk of VTE should beconsidered. If the balance of benefits and risks is considered to be negative a CHC should not beprescribed (see section 4.3).

Table 1: Risk factors for VTE

Risk factor Comment

Obesity (body mass index [BMI] over Risk increases substantially as BMI rises.30 kg/m²).

Particularly important to consider if other riskfactors also present.

Prolonged immobilisation, major surgery, any In these situations, it is advisable tosurgery to the legs or pelvis, neurosurgery, or discontinue use of the pill (in the case ofmajor trauma. elective surgery at least four weeks in advance)and not resume until two weeks after completeremobilisation. Another method ofcontraception should be used to avoidunintentional pregnancy.

Antithrombotic treatment should be consideredif Drovelis has not been discontinued inadvance.

Note: temporary immobilisation including airtravel > 4 hours can also be a risk factor for

VTE, particularly in women with other riskfactors.

Positive family history (VTE ever in a sibling If a hereditary predisposition is suspected, theor parent especially at a relatively early age, woman should be referred to a specialist fore.g. before 50 years). advice before deciding about any CHC use.

1These incidences were estimated from the totality of the epidemiological study data, using relative risks for the differentmedicinal products compared with levonorgestrel-containing CHCs.2 Mid-point of range of 5-7 per 10 000 women-years, based on a relative risk for CHCs containing levonorgestrel versus non-use of approximately 2.3 to 3.6.

Risk factor Comment

Other medical conditions associated with VTE. Cancer, systemic lupus erythematosus,haemolytic uraemic syndrome, chronicinflammatory bowel disease (Crohn's diseaseor 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 theonset or progression of venous thrombosis.

The increased risk of thromboembolism in pregnancy, and particularly the 6-week period of thepuerperium, 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 thehealthcare 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 bemisinterpreted 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 ofan extremity.

If the occlusion occurs in the eye symptoms can range from painless blurring of vision which canprogress 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 arterialthromboembolism (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 usersincreases in women with risk factors (see table 2). Drovelis is contraindicated if a woman has oneserious or multiple risk factors for ATE that puts her at high risk of arterial thrombosis (seesection 4.3). If a woman has more than one risk factor, it is possible that the increase in risk is greaterthan the sum of the individual factors - in this case her total risk should be considered. If the balanceof 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 theywish to use a CHC. Women over 35 years of

Risk factor Commentage who continue to smoke should be stronglyadvised to use a different method ofcontraception.

Obesity (BMI over 30 kg/m2). Risk increases substantially as BMI increases.

Particularly important in women withadditional risk factors.

Positive family history (arterial If a hereditary predisposition is suspected, thethromboembolism ever in a sibling or parent woman should be referred to a specialist forespecially at relatively early age, e.g. below advice before deciding about any CHC use.50 years).

Migraine. An increase in frequency or severity ofmigraine during CHC use (which may beprodromal of a cerebrovascular event) may bea reason for immediate discontinuation.

Other medical conditions associated with Diabetes mellitus, hyperhomocysteinaemia,adverse vascular events. valvular heart disease and atrial fibrillation,dyslipoproteinaemia and systemic lupuserythematosus.

In the event of symptoms women should be advised to seek urgent medical attention and to inform thehealthcare 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, orbelow 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 theextent to which this finding is attributable to the confounding effects of sexual behaviour and otherfactors such as human papilloma virus (HPV).

With the use of the higher-dosed CHCs (50 mcg ethinylestradiol) the risk of endometrial and ovariancancer 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 containingethinylestradiol. The excess risk gradually disappears during the course of the 10 years after cessationof CHC use. Because breast cancer is rare in women under 40 years of age, the excess number ofbreast cancer diagnoses in current and recent CHC users is small in relation to the overall risk of breastcancer. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancersdiagnosed in never-users. The observed pattern of increased risk may be due to an earlier diagnosis ofbreast 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 inusers of CHCs containing ethinylestradiol. In isolated cases, these tumours have led to life-threateningintra-abdominal haemorrhages. Therefore, a hepatic tumour should be considered in the differentialdiagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhageoccur in women taking CHCs.

Hepatitis C

During clinical studies with patients treated for hepatitis C virus (HCV) infection with medicinalproducts containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, ALTelevations higher than 5 times the upper limit of normal occurred significantly more frequently inwomen using ethinylestradiol-containing medicinal products such as CHCs. Additionally, also inpatients treated with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, ALT elevationswere observed in women using ethinylestradiol-containing medications such as CHCs. Women usingmedicinal products containing oestrogens other than ethinylestradiol had a rate of ALT elevation similarto those not receiving any oestrogens; however, due to the limited number of women taking these otheroestrogens, caution is warranted for co-administration with the combination therapeutic regimenombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin and also the regimenglecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir. See also section 4.5.

Other conditions

The progestogen component in Drovelis, drospirenone, is an aldosterone antagonist with potassiumsparing properties. In most cases, no increase of potassium levels would be expected. In a clinical studywith drospirenone, however, in some patients with mild or moderate renal impairment and concomitantuse of potassium-sparing medicinal products, serum potassium levels increased slightly, but notsignificantly, during intake of 3 mg drospirenone for 14 days. Therefore, it is recommended to checkserum potassium during the first treatment cycle with Drovelis in patients presenting with renalinsufficiency and a pretreatment serum potassium in the upper reference range, and particularly duringconcomitant 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 ofpancreatitis when using CHCs.

Although small increases in blood pressure have been reported in many women taking CHCs, clinicallyrelevant increases are rare. A relationship between CHC use and clinical hypertension has not beenestablished. 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 withantihypertensive 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 tocholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemicsyndrome; 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 untilmarkers of liver function return to normal. Recurrence of cholestatic jaundice which occurred first duringpregnancy 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 noevidence for a need to alter the therapeutic regimen in diabetics using low-dose CHCs (containing< 50 mcg ethinylestradiol). However, diabetic women should be carefully observed, particularly in theearly stage of CHC use.

Worsening of endogenous depression, of epilepsy, of Crohn’s disease and ulcerative colitis has beenreported during CHC use.

Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use (seesection 4.8). Depression can be serious and is a well-known risk factor for suicidal behaviour andsuicide. Women should be advised to contact their physician in case of mood changes and depressivesymptoms, including shortly after initiating the treatment.

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Womenwith a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking

CHCs.

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 physicalexamination should be performed, guided by the contraindications (see section 4.3) and warnings (seesection 4.4). It is important to draw a woman’s attention to the information on venous and arterialthrombosis, 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 shouldalso be instructed to carefully read the user leaflet and to adhere to the advice given. The frequencyand nature of examinations should be based on established practice guidelines and be adapted to theindividual woman.

Women should be advised that hormonal contraceptives do not protect against humanimmunodeficiency virus (HIV) infection and/or acquired immunodeficiency syndrome (AIDS) andother sexually transmitted diseases.

Reduced efficacy

The efficacy of CHCs may be reduced in the event of missed tablets (see section 4.2), gastrointestinaldisturbances during pink active tablet taking (see section 4.2) or concomitant medicinal products (seesection 4.5).

Cycle control

With all CHCs, unscheduled bleeding (spotting or bleeding) may occur, especially during the firstmonths of use. Therefore, the evaluation of any irregular bleeding is only meaningful after anadaptation interval of about three cycles. Unscheduled bleeding or spotting occurred in 14% to 20% ofwomen using Drovelis. Most of these episodes concerned spotting only.

If bleeding irregularities persist or occur after previously regular cycles, then non-hormonal causesshould be considered, and adequate diagnostic measures are indicated to exclude malignancy orpregnancy. These may include curettage.

In a small percentage of women (6-8%), withdrawal bleeding may not occur during the placebo tabletphase. If absence of withdrawal bleeding occurs and Drovelis has been taken according to theinstructions as described in section 4.2, pregnancy is unlikely. However, pregnancy must be ruled outbefore Drovelis use is continued, if Drovelis has not been taken as directed, or if two consecutivewithdrawal bleeds do not occur.

The use of contraceptive steroids may influence the results of certain laboratory tests, includingbiochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier)proteins, e.g. corticosteroid binding globulin (CBG) and lipid/lipoprotein fractions, parameters ofcarbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remainwithin the normal laboratory range. Drospirenone causes an increase in plasma renin activity andplasma aldosterone induced by its mild anti-mineralocorticoid activity.

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’.