ZOELY 2.5mg / 1.5mg film-coated tablets medication leaflet

Zoely 2.5 mg/1.5 mg film-coated tablets

Each white active tablet contains 2.5 mg nomegestrol acetate and 1.5 mg estradiol (as hemihydrate).

Each yellow placebo tablet does not contain active substances.

Each white active tablet contains 57.7 mg of lactose monohydrate.

Each yellow placebo tablet contains 61.8 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

The active tablet is white, round and coded ‘ne’ on both sides.

The placebo tablet is yellow, round and coded ‘p’ on both sides.

Oral contraception.

The decision to prescribe Zoely should take into consideration the individual woman’s current riskfactors, particularly those for venous thromboembolism (VTE), and how the risk of VTE with Zoelycompares with other combined hormonal contraceptives (CHCs) (see sections 4.3 and 4.4).

One tablet is to be taken daily for 28 consecutive days. Each pack starts with 24 white active tablets,followed by 4 yellow placebo tablets. A subsequent pack is started immediately after finishing theprevious pack, without a break in daily tablet intake and irrespective of presence or absence ofwithdrawal bleeding. Withdrawal bleeding usually starts on day 2-3 after intake of the last white tabletand may not have finished before the next pack is started. See ‘Cycle control’ in section 4.4.

Although data in renal impaired patients are not available, renal impairment is unlikely to affect theelimination of nomegestrol acetate and estradiol.

No clinical studies have been performed in patients with hepatic insufficiency. Since the metabolismof steroid hormones might be impaired in patients with severe hepatic disease, the use of Zoely inthese women is not indicated as long as liver function values have not returned to normal (seesection 4.3).

Safety and efficacy have not been established in adolescents under 18 years of age. There is norelevant use of Zoely in children and pre-menarchal adolescents.

Oral use.

How to take Zoely

Tablets must be taken every day at about the same time without regard to meals. Tablets should betaken with some liquid as needed, and in the order as directed on the blister. Stickers marked with the7 days of the week are provided. The woman should choose the sticker that starts with the day shebegins taking the tablets and stick it on the blister.

How to start Zoely

No preceding hormonal contraceptive use (in the past month)

Tablet-taking has to start on day 1 of the woman’s menstrual cycle (i.e. the first day of her menstrualbleeding). When doing so, no additional contraceptive measures are necessary.

Changing from a CHC (combined oral contraceptive (COC), vaginal ring or transdermal patch)

The woman should start with Zoely preferably on the day after the last active tablet-taking (the lasttablet containing the active substances) of her previous COC, but at the latest on the day following theusual tablet-free or placebo tablet interval of her previous COC. In case a vaginal ring or transdermalpatch has been used, the woman should start using Zoely preferably on the day of removal, but at thelatest when the next application would have been due.

Changing from a progestogen-only-method (minipill, implant, injectable) or from ahormone-medicated intra uterine system (IUS)

The woman may switch any day from the minipill and Zoely should be started on the next day. Animplant or IUS may be removed any day, and Zoely should be started on the day of its removal. Whenchanging from an injectable, Zoely should be started on the day when the next injection would havebeen due. In all of these cases, the woman should be advised to additionally use a barrier method untilshe has completed 7 days of uninterrupted white active table-taking.

Following first-trimester abortion

The woman may start the tablet-taking immediately. When doing so, no additional contraceptivemeasures are necessary.

Following delivery or second-trimester abortion

The woman should be advised to start the tablet-taking between day 21 and 28 after delivery orsecond-trimester abortion. When starting later, the woman should be advised to additionally use abarrier method until she has completed 7 days of uninterrupted white active tablet-taking. However, ifintercourse has already occurred, pregnancy should be excluded before the actual start of COC use orthe woman has to wait for her first menstrual period.

For breast-feeding women see section 4.6.

Management of missed tablets

The following advice only refers to missed white active tablets:

If the woman is less than 24 hours late in taking any active tablet, contraceptive protection is notreduced. The woman should take the tablet as soon as she remembers and should take further tablets atthe usual time.

If the woman is 24 or more hours late in taking any active tablet, contraceptive protection may bereduced. The management of missed tablets can be guided by the following two basic rules:

* 7 days of uninterrupted white active tablet-taking are required to attain adequate suppression ofthe hypothalamic-pituitary-ovarian-axis.

* The more white active tablets are missed and the closer the missed tablets are to the 4 yellowplacebo tablets, the higher the risk of a pregnancy.

Day 1-7

The woman should take the last missed white tablet as soon as she remembers, even if this meanstaking two tablets at the same time. She then continues to take tablets at her usual time. In addition, abarrier method such as a condom should be used until she has completed 7 days of uninterrupted whitetablet-taking. If intercourse took place in the preceding 7 days, the possibility of a pregnancy shouldbe considered.

Day 8-17

The woman should take the last missed white tablet as soon as she remembers, even if this meanstaking two tablets at the same time. She then continues to take tablets at her usual time. Provided thatthe woman has taken her tablets correctly in the 7 days preceding the first missed tablet, there is noneed to use extra contraceptive precautions. However, if she has missed more than 1 tablet, the womanshould be advised to use extra precautions until she has completed 7 days of uninterrupted whitetablet-taking.

Day 18-24

The risk of reduced reliability is imminent because of the forthcoming yellow placebo tablet phase.

However, by adjusting the tablet-intake schedule, reduced contraceptive protection can still beprevented. By adhering to either of the following two options, there is therefore no need to use extracontraceptive precautions, provided that in the 7 days preceding the first missed tablet the woman hastaken all tablets correctly. If this is not the case, she should follow the first of these two options anduse extra precautions for the next 7 days as well.1. The woman should take the last missed tablet as soon as she remembers, even if this meanstaking two tablets at the same time. She then continues to take tablets at her usual time until theactive tablets are used up. The 4 placebo tablets from the last row must be discarded. The nextblister pack must be started right away. The woman is unlikely to have a withdrawal bleedinguntil the end of the active tablets section of the second pack, but she may experience spotting orbreakthrough bleeding on tablet-taking days.

2. The woman may also be advised to discontinue active tablet-taking from the current blisterpack. She should then take placebo tablets from the last row for a maximum of 3 days such thatthe total number of placebo plus missed white active tablets is not more than 4, andsubsequently continue with the next blister pack.

If the woman missed tablets and subsequently has no withdrawal bleeding in the placebo tablet phase,the possibility of a pregnancy should be considered.

Please note: If the woman is not sure about the number or colour of tablets missed and what advice tofollow, a barrier method should be used until she has completed 7 days of uninterrupted white activetablet-taking.

The following advice only refers to missed yellow placebo tablets:

Contraceptive protection is not reduced. Yellow tablets from the last (4th) row of the blister can bedisregarded. However, the missed tablets should be discarded to avoid unintentionally prolonging theplacebo tablet phase.

Advice in case of gastro-intestinal disturbances

In case of severe gastro-intestinal disturbance (e.g., vomiting or diarrhoea), absorption of the activesubstances may not be complete and additional contraceptive measures should be taken.

If vomiting occurs within 3-4 hours after white tablet-taking, the tablet should be considered as missedand a new tablet should be taken as soon as possible. The new tablet should be taken within 24 hoursof the usual time of tablet-taking if possible. The next tablet should then be taken at the usual time. If24 or more hours have passed since last tablet intake, the advice concerning missed tablets, as given insection 4.2 'Management of missed tablets', is applicable. If the woman does not want to change hernormal tablet-taking schedule, she has to take the extra white tablet(s) from another pack.

How to shift periods or how to delay a period

To delay a period the woman should continue with another blister pack of Zoely without taking theyellow placebo tablets from her current pack. The extension can be carried on for as long as wisheduntil the end of the white active tablets in the second pack. Regular intake of Zoely is then resumedafter the yellow placebo tablets have been taken of the second pack. During the extension the womanmay experience breakthrough-bleeding or spotting.

To shift her periods to another day of the week than the woman is used to with her current scheme, shecan be advised to shorten her forthcoming yellow placebo tablet phase with a maximum of 4 days. Theshorter the interval, the higher the risk that she does not have a withdrawal bleeding and mayexperience breakthrough-bleeding and spotting during the subsequent pack (just as when delaying aperiod).

CHCs must not be used in the following conditions. Should any of the conditions appear for the firsttime during Zoely use, the medicinal product should be stopped immediately.

* Presence or risk of venous thromboembolism (VTE)o Venous thromboembolism - current VTE (on anticoagulants) or history of (e.g. deepvenous thrombosis [DVT] or pulmonary embolism [PE]).

o Known hereditary or acquired predisposition for venous thromboembolism, such asactivated protein C (APC)-resistance (including Factor V Leiden),antithrombin-III-deficiency, protein C deficiency, protein S deficiency.

o Major surgery with prolonged immobilisation (see section 4.4).o A high risk of venous thromboembolism due to the presence of multiple risk factors (seesection 4.4).

* Presence or risk of arterial thromboembolism (ATE)o Arterial thromboembolism - current ATE, history of ATE (e.g. myocardial infarction) orprodromal condition (e.g. angina pectoris).

o Cerebrovascular disease - current stroke, history of stroke or prodromal condition (e.g.transient ischaemic attack [TIA]).

o Known hereditary or acquired predisposition for arterial thromboembolism, such ashyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies,lupus anticoagulant).

o History of migraine with focal neurological symptoms.o A high risk of arterial thromboembolism due to multiple risk factors (see section 4.4) orto the presence of one serious risk factor such as:

* diabetes mellitus with vascular symptoms;

* severe hypertension;

* severe dyslipoproteinaemia.

* Pancreatitis or a history thereof if associated with severe hypertriglyceridaemia.

* Presence or history of severe hepatic disease as long as liver function values have not returnedto normal.

* Presence or history of liver tumours (benign or malignant).

* Known or suspected sex steroid-influenced malignancies (e.g., of the genital organs or thebreasts).

* Presence or history of meningioma.

* Undiagnosed vaginal bleeding.

* Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Warnings

If any of the conditions or risk factors mentioned below is present, the suitability of Zoely should bediscussed with the woman.

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 Zoely should be discontinued.

All data presented below are based upon epidemiological data obtained with CHCs containingethinylestradiol and apply to Zoely.

Risk of venous thromboembolism (VTE)

* The use of any combined hormonal contraceptive (CHC) increases the risk of venousthromboembolism (VTE) compared with no use. Products that contain levonorgestrel,norgestimate or norethisterone are associated with the lowest risk of VTE. Zoely may havea risk of VTE in the same range as observed with CHC containing levonorgestrel. Thedecision to use any product other than one known to have the lowest VTE risk should betaken only after a discussion with the woman to ensure she understands the risk of VTEwith CHCs, how her current risk factors influence this risk, and that her VTE risk ishighest in the first ever year of use. There is also some evidence that the risk is increasedwhen 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 farhigher, depending on her underlying risk factors (see below).

* Epidemiological studies in women who use low dose (< 50 micrograms ethinylestradiol) CHChave found that out of 10,000 women between 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 61 willdevelop a VTE in one year.

* The number of VTEs per year with low dose CHCs is fewer than the number expected inwomen 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 awoman with additional risk factors, particularly if there are multiple risk factors (see table).

Zoely 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).

1 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

Table: Risk factors for VTE

Risk factor Comment

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

Particularly important to consider if other riskfactors also present.

Prolonged immobilisation, major surgery, any In these situations it is advisable to discontinuesurgery to the legs or pelvis, neurosurgery, or use of the pill (in the case of elective surgery atmajor trauma least four weeks in advance) and not resumeuntil two weeks after complete remobilisation.

Note: Temporary immobilisation including air Another method of contraception should be usedtravel > 4 hours can also be a risk factor for to avoid unintentional pregnancy.

VTE, particularly in women with other riskfactors. Antithrombotic treatment should be consideredif Zoely has not been discontinued in advance.

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

Other medical conditions associated with VTE Cancer, systemic lupus erythematosus,haemolytic uraemic syndrome, chronicinflammatory bowel disease (Crohn's disease orulcerative colitis) and sickle cell disease

Increasing age Particularly above 35 years

* There is no consensus about the possible role of varicose veins and superficial thrombophlebitisin the onset 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).

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 deep vein thrombosis (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 pulmonary embolism (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 arterial thromboembolism (ATE)

Epidemiological studies have associated the use of CHCs with an increased risk for arterialthromboembolism (myocardial infarction) or for cerebrovascular accident (e.g., transient ischaemicattack, 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). Zoely is contraindicated if a woman has one seriousor multiple risk factors for ATE that puts her at high risk of arterial thrombosis (see section 4.3). If awoman has more than one risk factor, it is possible that the increase in risk is greater than the sum ofthe individual factors - in this case her total risk should be considered. If the balance of benefits andrisks is considered to be negative a CHC should not be prescribed (see section 4.3).

Table: 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 whocontinue to smoke should be strongly advised touse a different method of contraception.

Obesity (body mass index 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 50) advice before deciding about any CHC use.

Migraine An increase in frequency or severity of migraineduring CHC use (which may be prodromal of acerebrovascular event) may be a reason forimmediate 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 a 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 COCs (> 5 years) has been reported insome epidemiological studies, but there continues to be controversy about the extent to whichthis finding is attributable to the confounding effects of sexual behaviour and other factors suchas human papilloma virus (HPV). No epidemiological data on the risk of cervical cancer inusers of Zoely are available.

* With the use of the higher-dosed COCs (50 micrograms ethinylestradiol) the risk of endometrialand ovarian cancer is reduced. Whether this also applies to 17β-estradiol-containing COCsremains to be confirmed.

* A meta-analysis from 54 epidemiological studies reported that there is a slightly increasedrelative risk (RR=1.24) of having breast cancer diagnosed in women who are currently using

COCs. The excess risk gradually disappears during the course of the 10 years after cessation of

COC use. Because breast cancer is rare in women under 40 years of age, the excess number ofbreast cancer diagnoses in current and recent COC users is small in relation to the overall risk ofbreast cancer. The breast cancers diagnosed in ever-users tend to be less advanced clinicallythan the cancers diagnosed in never-users. The observed pattern of increased risk may be due toan earlier diagnosis of breast cancer in COC users, the biological effects of COCs or acombination of both.

* In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have beenreported in users of COCs. In isolated cases, these tumours have led to life-threateningintra-abdominal haemorrhages. Therefore, a hepatic tumour should be considered in thedifferential diagnosis when severe upper abdominal pain, liver enlargement or signs ofintra-abdominal haemorrhage occur in women taking COCs.

Meningioma

The occurrence of meningioma (single and multiple) has been reported with prolonged use (severalyears) of nomegestrol monotherapy at doses of 3.75 mg or 5 mg daily and higher. If a meningioma isdiagnosed in a patient treated with Zoely, treatment should be stopped (see section 4.3).

Hepatitis C

* During clinical trials with the hepatitis C virus (HCV) combination regimenombitasvir/paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 timesthe upper limit of normal (ULN) were significantly more frequent in women usingethinylestradiol-containing medicinal products such as CHCs. Additionally, also in patients treatedwith glecaprevir/pibrentasvir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs. Women using medicinal products containing oestrogensother than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those notreceiving any oestrogens; however, due to the limited number of women taking these otheroestrogens, caution is warranted for co-administration with the combination drug regimenombitasvir/paritaprevir/ritonavir with or without dasabuvir and also the regimenglecaprevir/pibrentasvir. See section 4.5.

Other conditions

* Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk ofpancreatitis when using COCs.

* Although small increases in blood pressure have been reported in many women taking COCs,clinically relevant increases are rare. A relationship between COC use and clinical hypertensionhas not been established. However, if a sustained clinically significant hypertension developsduring the use of a COC, then it is prudent for the physician to suspend the intake of the tabletsand treat the hypertension. Where considered appropriate, COC use may be resumed ifnormotensive values can be achieved with antihypertensive therapy.

* The following conditions have been reported to occur or deteriorate with both pregnancy and

COC use, but the evidence of an association with COC use is inconclusive: jaundice and/orpruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus;haemolytic uraemic syndrome; Sydenham’s chorea; herpes gestationis; otosclerosis-relatedhearing loss.

* Exogenous oestrogens may induce or exacerbate symptoms of hereditary and acquiredangioedema.

* Acute or chronic disturbances of liver function may necessitate the discontinuation of COC useuntil markers of liver function return to normal. Recurrence of cholestatic jaundice which occurredfirst during pregnancy or previous use of sex steroids necessitates the discontinuation of COCs.

* Although COCs may have an effect on peripheral insulin resistance and glucose tolerance, thereis no evidence for a need to alter the therapeutic regimen in diabetics using low-dose COCs(containing < 0.05 mg ethinylestradiol). However, diabetic women should be carefully observedwhile taking a COC, especially in the first months of use.

* Crohn’s disease, ulcerative colitis, and worsening of depression have been associated with COCuse.

* 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 radiationwhilst taking COCs.

* Depressed mood and depression are well-known undesirable effects of hormonal contraceptiveuse (see section 4.8). Depression can be serious and is a well-known risk factor for suicidalbehaviour and suicide. Women should be advised to contact their physician in case of moodchanges and depressive symptoms, including shortly after initiating the treatment.

Prior to the initiation or reinstitution of Zoely use a complete medical history (including familyhistory) should be taken and pregnancy must be ruled out. Blood pressure should be measured and aphysical examination should be performed, guided by the contraindications (see section 4.3) andwarnings (see section 4.4). It is important to draw a woman’s attention to the information on venousand arterial thrombosis, including the risk of Zoely compared with other CHCs, the symptoms of VTEand 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 advicegiven. The frequency and nature of examinations should be based on established practice guidelinesand be adapted to the individual woman.

Women should be advised that hormonal contraceptives do not protect against humanimmunodeficiency virus (HIV) infections (which can cause acquired immunodeficiency syndrome[AIDS]) and other sexually transmitted diseases.

Reduced efficacy

The efficacy of COCs may be reduced in the event of e.g., missed tablets (see section 4.2),gastro-intestinal disturbances during active tablet-taking (see section 4.2) or use of concomitantmedicinal products that decrease the plasma concentrations of nomegestrol acetate and/or estradiol(see section 4.5).

Cycle control

With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially duringthe first months of use. Therefore, the evaluation of any irregular bleeding is only meaningful after anadaptation interval of about 3 cycles. The percentage of women using Zoely experiencing intracyclicbleeding after this adaptation period ranged from 15-20 %.

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.

The duration of the withdrawal bleeding in women using Zoely is on average 3-4 days. Users of Zoelymay also miss their withdrawal bleeding although not being pregnant. During clinical trials, absence ofwithdrawal bleeding ranged over the cycles 1-12 from 18 % to 32 %. In such cases, absence ofwithdrawal bleeding was not associated with a higher occurrence of breakthrough bleeding/spotting inthe subsequent cycles. 4.6 % of the women did not have a withdrawal bleeding in the first three cyclesof use and the occurrences of absence of withdrawal bleeding in the later cycles of use were high inthis subgroup, ranging from 76 % to 87 % of women. 28 % of the women experienced absence ofwithdrawal bleeding in at least one of the cycles 2, 3 and 4, associated with higher occurrences ofabsence of withdrawal bleeding in the later cycles of use, ranging from 51 % to 62 %.

If absence of withdrawal bleeding occurs and Zoely has been taken according to the instructions asdescribed in section 4.2, it is unlikely that the woman is pregnant. However, pregnancy must be ruledout before Zoely use is continued, if Zoely has not been taken as directed or if two consecutivewithdrawal bleedings are missed.

It is unknown whether the amount of estradiol in Zoely is sufficient to maintain adequate levels ofestradiol in adolescents, especially for bone mass accrual (see section 5.2).

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 and lipid/lipoprotein fractions, parameters ofcarbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remainwithin the normal laboratory range.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency orglucose-galactose malabsorption should not take this medicinal product.

Note: The prescribing information of concomitant medicinal products should be consulted to identifypotential interactions.

Influence of other medicinal products on Zoely

Interactions between oral contraceptives and enzyme-inducing medicinal products may lead tobreakthrough bleeding and/or contraceptive failure.

Hepatic metabolism: Interactions can occur with substances that induce CYP450 enzymes, resulting inreduced concentrations of sex hormones and decreased effectiveness of combined oral contraceptives,including Zoely. These substances are represented mostly with anticonvulsants (e.g. carbamazepine,topiramate, phenytoin, phenobarbital, primidone, oxcarbazepine, felbamate); anti-infective drugs (e.g.rifampicin, rifabutin, griseofulvin); St. John’s wort; bosentan and HIV or Hepatitis C virus (HCV)protease inhibitors (e.g. ritonavir, boceprevir, telaprevir) and non-nucleoside reverse transcriptaseinhibitors (e.g. efavirenz).

Enzyme induction can occur after a few days of treatment. Maximal enzyme induction is generallyobserved within a few weeks. After drug therapy is discontinued, enzyme induction can last for about28 days.

A barrier contraceptive method should also be used during the concomitant use of an enzyme inducer,and for 28 days after its discontinuation. In case of long-term treatment with hepatic enzyme-inducingsubstances another method of contraception should be considered.

If concomitant drug administration runs beyond the end of the active tablets in the current blister pack,the next blister pack should be started right away without the usual placebo tablet interval.

Concomitant administration of strong (e.g. ketoconazole, itraconazole, clarithromycin) or moderate(e.g. fluconazole, diltiazem, erythromycin) CYP3A4 inhibitors may increase the serum concentrationsof oestrogens or progestogens.

Medicinal product interaction studies were not performed with Zoely, but two studies with rifampicinand ketoconazole, respectively, were performed with a higher dosed nomegestrol acetate-estradiolcombination (nomegestrol acetate 3.75 mg + 1.5 mg estradiol) in post-menopausal women.

Concomitant use of rifampicin decreases the AUC0-∞ of nomegestrol acetate by 95 % and increases the

AUC0-tlast of estradiol by 25 %. Concomitant use of ketoconazole (200 mg single dose) does notmodify estradiol metabolism whereas increases in the peak concentration (85 %) and AUC0-∞ (115 %)of nomegestrol acetate were observed, which were of no clinical relevance. Similar conclusions areexpected in women of childbearing potential.

Influence of Zoely on other medicinal products

Contraceptives containing ethinylestradiol may decrease the concentrations of lamotrigine byapproximately 50%. Attention should be paid, notably when introducing a combined contraceptive,even with estradiol, in a well-equilibrated woman given lamotrigine.

During clinical trials with the HCV combination drug regimen ombitasvir/paritaprevir/ritonavir withand without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) weresignificantly more frequent in women using ethinylestradiol-containing medicinal products such as

CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol, such asestradiol, had a rate of ALT elevation similar to those not receiving any oestrogens; however, due tothe limited number of women taking these other oestrogens, caution is warranted for co-administrationwith the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir andalso the regimen with glecaprevir/pibrentasvir (see section 4.4).

Zoely is not indicated during pregnancy.

If pregnancy occurs while taking Zoely, further intake should be stopped. Most epidemiologicalstudies have revealed neither an increased risk of birth defects in infants born to women who usedethinylestradiol-containing COCs prior to pregnancy, nor a teratogenic effect whenethinylestradiol-containing COCs were taken inadvertently during early pregnancy.

Clinical data on a limited number of exposed pregnancies indicate no adverse effect of Zoely on thefoetus or neonate.

In animal studies, reproductive toxicity has been observed with the nomegestrol acetate/estradiolcombination (see preclinical safety data in section 5.3).

The increased risk of VTE during the postpartum period should be considered when re-starting Zoely(see section 4.2 and 4.4).

Small amounts of the contraceptive steroids and/or their metabolites may be excreted with the breastmilk, but there is no evidence that this adversely affects infant health.

Breast-feeding may be influenced by COCs as they may reduce the quantity and change thecomposition of breast milk. Therefore, the use of COCs should not be recommended until the breast-feeding mother has completely weaned her child and an alternative method of contraception should beproposed to women wishing to breastfeed.

Zoely is indicated for the prevention of pregnancy. For information on return to fertility, seesection 5.1.

Zoely has no or negligible influence on the ability to drive and use machines.

Six multi-centre clinical trials of up to one-year duration were used to evaluate safety of Zoely. In total3,434 women, aged 18-50, were enrolled and completed 33,828 cycles.

Most commonly reported adverse reactions in these clinical trials were acne (15.4%) and withdrawalbleeding irregular (9.8%).

An increased risk for venous and arterial thromboembolism, causative of serious adverse events hasbeen observed with the use of CHCs (see section 4.4)

Possibly related adverse reactions that have been reported in clinical trials or during post-marketinguse with Zoely are listed in the table below.

Adverse reactions are listed according to the MedDRA system organ class and ranked under frequencygroupings using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10),uncommon (≥ 1/1,000 to < 1/100) and rare (≥ 1/10,000 to < 1/1,000).

Table: List of adverse reactions

Adverse reaction in MedDRA Term1

System organ class Very common Common Uncommon Rare

Metabolism and increased decreasednutrition disorders appetite, fluid appetiteretention

Psychiatric disorders decreased increased libidolibido,depression/depressedmood, moodaltered

Nervous system headache, cerebrovasculardisorders migraine accident,transientischaemic attack,disturbance inattention

Adverse reaction in MedDRA Term1

System organ class Very common Common Uncommon Rare

Eye disorders contact lensintolerance/dryeye

Vascular disorders hot flush venousthromboembolism

Gastrointestinal nausea abdominal dry mouthdisorders distension

Hepatobiliary cholelithiasis,disorders cholecystitis

Skin and acne hyperhydrosis, chloasma,subcutaneous tissue alopecia, hypertrichosisdisorders pruritus, dryskin, seborrhea

Musculoskeletal and sensation ofconnective tissue heavinessdisorders

Reproductive system abnormal metrorrhagia, hypomenorrhoea, vaginal odour,and breast disorders withdrawal menorrhagia, breast swelling, vulvovaginalbleeding breast pain, galactorrhoea, discomfortpelvic pain uterine spasm,premenstrualsyndrome, breastmass,dyspareunia,vulvovaginaldryness

General disorders and irritability, hungeradministration site oedemaconditions

Investigations weight hepatic enzymeincreased increased1The most appropriate MedDRA term to describe a certain adverse reaction is listed. Synonyms or relatedconditions are not listed, but should be taken into account as well.

In addition to the above-mentioned adverse reactions, hypersensitivity reactions have been reported in

Zoely users (frequency unknown).

An increased risk of arterial and venous thrombotic and thromboembolic events, including myocardialinfarction, stroke, transient ischaemic attacks, venous thrombosis and pulmonary embolism has beenobserved in women using CHCs, which are discussed in more detail in section 4.4.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Multiple doses up to five times the daily dose of Zoely and single doses up to 40 times the daily doseof nomegestrol acetate alone have been used in women without safety concern. On the basis of generalexperience with combined oral contraceptives, symptoms that may occur are: nausea, vomiting and, inyoung girls, slight vaginal bleeding. There are no antidotes and further treatment should besymptomatic.

Pharmacotherapeutic group: Sex hormones and modulators of the genital system, progestogens andestrogens, fixed combinations, ATC code: G03AA14.

Nomegestrol acetate is a highly selective progestogen derived from the naturally occurring steroidhormone, progesterone. Nomegestrol acetate has a strong affinity for the human progesterone receptorand has an anti-gonadotropic activity, a progesterone receptor-mediated anti-oestrogenic activity, amoderate anti-androgenic activity, and is devoid of any oestrogenic, androgenic, glucocorticoid ormineralocorticoid activity.

The oestrogen contained in Zoely is 17β-estradiol, an oestrogen identical to the endogenous human17β-estradiol.

The contraceptive effect of Zoely is based on the interaction of various factors, the most important ofwhich are seen as the inhibition of ovulation and the changes in the cervical secretion.

In two randomised, open-label, comparative efficacy-safety trials, more than 3,200 women have beentreated for up to 13 consecutive cycles with Zoely and more than 1,000 women with drospirenone3 mg - ethinylestradiol 30 μg (21/7 regimen).

In the Zoely group, acne was reported by 15.4 % of the women (versus 7.9 % in the comparatorgroup), weight increased was reported by 8.6 % of the women (versus 5.7 % in the comparator group),and abnormal withdrawal bleeding (predominantly absence of withdrawal bleeding) was reported by10.5 % of the women (versus 0.5 % in the comparator group).

In the clinical trial performed with Zoely in the European Union the following Pearl Indices for theage class 18-35 years were calculated:

Method failure: 0.40 (upper limit 95 % confidence interval 1.03).

Method and user failure: 0.38 (upper limit 95 % confidence interval 0.97).

In the clinical trial performed with Zoely in the United States the following Pearl Indices for the ageclass 18-35 years were calculated:

Method failure: 1.22 (upper limit 95 % confidence interval 2.18).

Method and user failure: 1.16 (upper limit 95 % confidence interval 2.08).

In a randomised, open label trial, 32 women were treated for 6 cycles with Zoely.

After discontinuation of Zoely, return to ovulation in the first 28 days after last tablet intake wasobserved in 79 % of the women.

Endometrial histology was investigated in a subgroup of women (n=32) in one clinical study after13 cycles of treatment. There were no abnormal results.

No data on efficacy and safety are available in adolescents below 18 years. Available pharmacokineticdata are described in section 5.2.

Nomegestrol acetate

Orally administered nomegestrol acetate is rapidly absorbed.

Maximum plasma concentrations of nomegestrol acetate of about 7 ng/mL are reached at 2 h aftersingle administration. The absolute bioavailability of nomegestrol acetate after a single dose is 63 %.

No clinically relevant effect of food was observed on the bioavailability of nomegestrol acetate.

Nomegestrol acetate is extensively bound to albumin (97-98 %), but does not bind to sex hormonebinding globulin (SHBG) or corticoid binding globulin (CBG). The apparent volume of distribution ofnomegestrol acetate at steady-state is 1,645 ± 576 L.

Nomegestrol acetate is metabolized into several inactive hydroxylated metabolites by livercytochrome P450 enzymes, mainly CYP3A4 and CYP3A5 with possible contribution of CYP2C19and CYP2C8. Nomegestrol acetate and its hydroxylated metabolites undergo extensive phase 2metabolism to form glucuronide- and sulphate conjugates. The apparent clearance at steady state is26 L/h.

The elimination half-life (t1/2) is 46 h (ranging from 28-83 h) at steady state. The elimination half-lifeof metabolites was not determined.

Nomegestrol acetate is excreted via urine and faeces. Approximately 80 % of the dose is excreted inurine and faeces within 4 days. Excretion of nomegestrol acetate was nearly complete after 10 daysand amounts excreted were higher in faeces than in urine.

Dose-linearity was observed in the range 0.625-5 mg (assessed in fertile and post-menopausalwomen).

Steady-state conditions

The pharmacokinetics of nomegestrol acetate are not influenced by SHBG.

Steady-state is achieved after 5 days. Maximum plasma concentrations of nomegestrol acetate of about12 ng/mL are reached 1.5 h after dosing. Average steady state plasma concentrations are 4 ng/mL.

Drug drug interactions

Nomegestrol acetate causes in vitro no notable induction or inhibition of any cytochrome P450enzymes and has no clinically relevant interaction with the P-gp transporter.

Estradiol

Estradiol is subject to a substantial first-pass effect after oral administration. The absolutebioavailability is about 1 %. No clinically relevant effect of food was observed on the bioavailabilityof estradiol.

The distribution of exogenous and endogenous estradiol is similar. Oestrogens are widely distributedin the body and are generally found in higher concentrations in the sex hormone target organs.

Estradiol circulates in the blood bound to SHBG (37 %) and to albumin (61 %), while onlyapproximately 1-2 % is unbound.

Oral exogenous estradiol is extensively metabolized. The metabolism of exogenous and endogenousestradiol is similar. Estradiol is rapidly transformed in the gut and the liver in several metabolites,mainly estrone, which are subsequently conjugated and undergo entero-hepatic circulation. There is adynamic equilibrium between estradiol, estrone and estrone-Sulfate due to various enzymatic activitiesincluding estradiol-dehydrogenases, sulfotransferases and aryl sulfatases. Oxidation of estrone andestradiol involves cytochrome P450 enzymes, mainly CYP1A2, CYP1A2 (extra hepatic), CYP3A4,

CYP3A5, and CYP1B1 and CYP2C9.

Estradiol is rapidly cleared from the circulation. Due to metabolism and enterohepatic circulation, alarge circulating pool of oestrogen sulfates and glucuronides is present. This results in a highlyvariable baseline-corrected elimination half-life of estradiol, which is calculated to be 3.6 ± 1.5 h, afterintravenous administration.

Steady-state conditions

Maximum serum concentrations of estradiol are about 90 pg/mL and are reached 6 h after dosing.

Average serum concentrations are 50 pg/mL and these estradiol levels correspond with the early andlate phase of a woman’s menstrual cycle.

Effect of renal impairment

No studies were performed to evaluate the effect of renal disease on the pharmacokinetics of Zoely.

Effect of hepatic impairment

No studies were conducted to evaluate the effect of hepatic disease on the pharmacokinetics of Zoely.

However, steroid hormones may be poorly metabolized in women with impaired liver function.

Ethnic groups

No formal studies were performed to assess pharmacokinetics in ethnic groups.

The pharmacokinetics of nomegestrol acetate (primary objective) after single oral dosing of Zoely inhealthy postmenarcheal female adolescents and adult subjects were similar. However, after single oraldosing, for the estradiol component (secondary objective), the exposure was 36 % lower in adolescentsversus adult subjects. The clinical relevance of this result is unknown.

Repeated dose toxicity studies with estradiol, nomegestrol acetate or combination have indicatedexpected oestrogenic and gestagen effects.

Reproductive toxicity studies performed with the combination have shown foetotoxicity which isconsistent with estradiol exposure.

Genotoxicity and carcinogenicity studies were not conducted with the combination. Nomegestrolacetate is not genotoxic.

However, it must be borne in mind that sex steroids can promote the growth of certainhormone-dependent tissues and tumours.

Tablet core (white active and yellow placebo film-coated tablets)

Lactose monohydrate

Microcrystalline cellulose (E460)

Crospovidone (E1201)

Talc (E553b)

Magnesium stearate (E572)

Colloidal anhydrous silica

Tablet coat (white active film-coated tablets)

Polyvinyl alcohol (E1203)

Titanium dioxide (E171)

Macrogol 3350

Talc (E553b)

Tablet coating (yellow placebo film-coated tablets)

Polyvinyl alcohol (E1203)

Titanium dioxide (E171)

Macrogol 3350

Talc (E553b)

Yellow iron oxide (E172)

Black iron oxide (E172)

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

PVC/aluminium blister containing 28 film-coated tablets (24 white active tablets and 4 yellow placebotablets).

Pack sizes: 28, 84, 168 and 364 film-coated tablets.

Not all pack sizes may be marketed.

COC tablets (including Zoely tablets) no longer required should not be disposed via wastewater or themunicipal sewage system. The hormonal active compounds in the tablets may have harmful effects ifreaching the aquatic environment. The tablets should be returned to a pharmacy or disposed of inanother safe way according to local requirements. These measures will help to protect theenvironment.

Theramex Ireland Limited3rd Floor, Kilmore House,

Park Lane, Spencer Dock,

Dublin 1

D01 YE64

Ireland

EU/1/11/690/001

EU/1/11/690/002

EU/1/11/690/003

EU/1/11/690/004

Date of first authorisation: 27 July 2011

Date of latest renewal: 10 May 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency: http://www.ema.europa.eu.