Zoely FC tablets

Oral contraception.

Posology
Tablets must be taken orally every day at about the same time without regard to meals, with some liquid as needed, and in the order as directed on the package. One tablet is to be taken daily for 28 consecutive days. Each pill pack starts with 24 white active tablets followed by 4 yellow placebo tablets (see Picture 1). A subsequent pack is started immediately after finishing the previous pack, without a break in daily tablet intake and irrespective of presence or absence of withdrawal bleeding. Withdrawal bleeding usually starts on day 2 to 3 after intake of the last white tablet and may not have finished before the next pack started.
How to start ZOELY
No preceding hormonal contraceptive use
Tablet-taking has to start on day 1 of the womanu2019s natural cycle (i.e., the first day of her menstrual bleeding). When doing so, no additional contraceptive measures are necessary. Starting on days 2 to 5 is allowed, but during the first pill pack a barrier contraceptive method should be used until the woman has completed 7 days of uninterrupted white tablet-taking (see Picture 1).
Changing from a combined hormonal contraceptive (combined oral contraceptive (COC), vaginal ring or transdermal patch)
The woman should start with ZOELY preferably on the day after the last tablet containing the active substance of her previous COC, but at least on the day following the usual tablet-free or placebo tablet interval of her previous COC. In case a vaginal ring or transdermal patch was used, the woman should start using ZOELY preferably on the day of removal, but at least when the next application would have been due. If the woman has been using her previous method consistently and correctly, and if it is reasonably certain that she is not pregnant, she may also switch on any day. The hormone-free interval of the previous method should never be extended beyond its recommended length.
Changing from a progestogen-only-method (minipill, implant, injectable) or from a hormone-medicated Intra-Uterine System (IUS)
The woman may switch on any day from the minipill and ZOELY should be started on the next day. An implant or IUS may be removed on any day, and ZOELY should be started on the day of its removal. When changing from an injectable, ZOELY should be started on the day when the next injection would have been due. In all of these cases, the woman should be advised to additionally use a barrier method until she has completed 7 days of uninterrupted white active tablet-taking.
Following first-trimester abortion
The woman may start ZOELY immediately. When doing so, no additional contraceptive measures are necessary.
Following delivery or second-trimester abortion
For breastfeeding women (see section 4.6). Women should be advised to start between day 21 and 28 after delivery or second-trimester abortion. When starting later, the woman should be advised to additionally use a barrier method of contraception for the first 7 days of white active tablet-taking. However, if intercourse has already occurred, pregnancy should be excluded before the actual start of ZOELY use or the woman has to wait for her first menstrual period. The increased risk of venous thromboembolism (VTE) during the postpartum period should be considered when restarting ZOELY (see section 4.4).
Management of missed tablets
The following advice only refers to missed white active tablets: If user is less than 24 hours late in taking any active tablet, contraceptive protection is not reduced. The woman should take the tablet as soon as she remembers and should take the subsequent tablets at the usual time. If she is 24 or more hours late in taking any active tablet, contraceptive protection may be reduced. The management of missed tablets can be guided by the following two basic rules:
u2022 7 days of uninterrupted u2018white active tabletu2019-taking are required to attain adequate suppression of the hypothalamic-pituitary-ovarian axis.
u2022 The more u2018white active tabletsu2019 are missed and the closer the missed tablets are to the 4 yellow placebo tablets, the higher the risk of a pregnancy.
Day 1 to 7
The user should take the last missed white tablet as soon as she remembers, even if this means taking 2 tablets at the same time. She then continues to take tablets at her usual time. A barrier contraceptive method should be used until she has completed 7 days of uninterrupted white tablet-taking. If intercourse took place in the preceding 7 days, the possibility of a pregnancy should be considered.
Day 8 to 17
The user should take the last missed white tablet as soon as she remembers even if this means taking 2 tablets at the same time. She then continues to take tablets at her usual time. Provided that the woman has taken her tablets correctly in the 7 days preceding the first missed tablet, there is no need to use additional contraceptive precautions. However, if she has missed more than 1 tablet, the woman should be advised to use additional contraceptive precautions until she has completed 7 days of uninterrupted white tablet-taking.
Day 18 to 24
The risk of reduced reliability is higher because of the forthcoming yellow placebo-tablet interval. However, by adjusting the tablet-intake schedule, reduced contraceptive protection can still be prevented. By adhering to either of the following two options, there is therefore no need to use additional contraceptive precautions, provided that in the 7 days preceding the first missed tablet the woman has taken all tablets correctly. If this is not the case, she should follow the first of these two options and use additional precautions for the next 7 days as well.
Option 1: The user should take the last missed tablet 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 until the active tablets are used up. The 4 placebo tablets from the last row must be discarded. The next blister pack must be started right away. The user is unlikely to have a withdrawal bleed until the end of the active tablets section of the second pack, but she may experience spotting or breakthrough bleeding on the tablet-taking days.
Option 2: The women may be advised to discontinue active tabletu2013taking from the current blister pack. She should then take placebo tablets from the last row for a maximum of 3 days, such that the total number of placebo plus missed active white tablets is not more than 4, and subsequently continue with the next blister pack. If the woman missed tablets and subsequently has no withdrawal bleed in the placebo tablet phase, the possibility of a pregnancy should be considered.
Please note: If the user is not sure about the number or colour of tablets missed and what advice to follow, a barrier contraceptive method should be used until she has completed 7 days of uninterrupted white active tablet-taking.
Yellow placebo tablets missed
Contraceptive protection is not reduced. Yellow tablets from the last (4th) row of the blister can be disregarded. However, the missed tablets should be discarded to avoid unintentionally prolonging the placebo tablet phase.
Advice in case of gastrointestinal disturbances
In case of severe gastrointestinal disturbance (e.g., vomiting or diarrhoea), absorption of the active substances may not be complete and additional contraceptive measures should be used. If vomiting occurs within 3 to 4 hours after white tablet-taking, the tablet should be considered as missed and a new tablet should be taken as soon as possible. The new tablet should be taken within 24 hours of the usual time of tablet-taking if possible. The next tablet should then be taken at the usual time. If 24 or more hours have passed since last tablet intake, the advice concerning missed tablets as given (see u2018Management of missed tabletsu2019), is applicable. If the woman does not want to change her normal 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 the yellow tablets from her current pack. The extension can be carried on until the end of the white tablets in the second pack. Regular intake of ZOELY is then resumed after the yellow placebo tablets of the second pack have been taken. During the extension period, the woman may experience breakthrough-bleeding or spotting. To shift her periods to another day of the week than the womanu2019s current scheme, she may be advised to shorten her forthcoming placebo tablet phase by a maximum of 4 days. The shorter the interval, the higher the risk that she does not have a withdrawal bleed and may experience breakthrough-bleeding and spotting during the subsequent pack (just as when delaying a period).

ZOELY should not be used in the presence of any of the conditions listed below. Should any of the following conditions appear for the first time during ZOELY use, the product should be stopped immediately:
u2022 Hypersensitivity to any of the active substances of ZOELY or to any of the other excipients listed in section 6.1.
u2022 Presence or risk of venous thromboembolism (VTE)
- Venous thromboembolism - current VTE (on anticoagulants) or history of (e.g., deep venous thrombosis (DVT), or pulmonary embolism (PE)).
- Known hereditary or acquired predisposition for venous thromboembolism, such as activated protein C (APC)-resistance (including Factor V Leiden), antithrombin-III- deficiency, protein C deficiency, protein S deficiency.
- Major surgery with prolonged immobilisation (see section 4.4).
- A high risk of venous thromboembolism due to the presence of multiple risk factors (see section 4.4).
u2022 Presence or risk of arterial thromboembolism (ATE)
- Arterial thromboembolism - current ATE, history of ATE (e.g., myocardial infarction) or prodromal condition (e.g., angina pectoris).
- Cerebrovascular disease u2013 current stroke, history of stroke or prodromal condition (e.g., transient ischaemic attack (TIA)).
- Known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant).
- History of migraine with focal neurological symptoms.
- A high risk of arterial thromboembolism due to multiple risk factors (see section 4.4) to the presence of one serious risk factor such as:
uf0a7 diabetes mellitus with vascular symptoms,
uf0a7 severe hypertension,
uf0a7 severe dyslipoproteinaemia.
u2022 Pancreatitis or a history thereof, if associated with severe hypertriglyceridaemia.
u2022 Presence or history of severe hepatic disease as long as liver function values have not returned to normal.
u2022 Presence or history of liver tumours (benign or malignant).
u2022 Known or suspected sex steroid-influenced malignancies (e.g., of the genital organs or the breasts).
u2022 Meningioma or history of meningioma.
u2022 Undiagnosed vaginal bleeding.
u2022 Known or suspected pregnancy (see section 4.6).

The decision to prescribe ZOELY should take into consideration the individual womanu2019s current risk factors, particularly those for venous thromboembolism (VTE), and how the risk of VTE with ZOELY compares with other combined hormonal contraceptives (CHCs) (see sections 4.3 and 4.4). If any of the conditions or risk factors mentioned below is present, the suitability of ZOELY should be discussed with the woman. In the event of aggravation, or first appearance of any of these conditions or risk factors, the woman should be advised to contact her medical practitioner to determine whether the use of ZOELY should be discontinued. All data presented below are based upon epidemiological data obtained with combined hormonal contraceptives (CHCs) containing ethinylestradiol and apply to ZOELY.
Depression and mood changes
Mood changes and depression are side effects reported with the use of hormonal containing products including ZOELY (see section 4.8). There is some evidence that the use of estrogen and/or progesterone/progestogen containing medicines may be associated with severe depression and a higher risk of suicidal thoughts/behaviours (e.g., talking about suicide, withdrawing from social contact, having mood swings, being preoccupied with death or violence, feeling hopeless about a situation, increasing use of alcohol/drugs doing self-destructive things, personality changes) and suicide. Prescribers should inform their patients to contact their doctor for advice if they experience mood changes and depression whilst on treatment with ZOELY.
Risk of venous thromboembolism (VTE)
u2022 The use of combined hormonal contraceptives (CHCs) such as ZOELY carries an increased risk of venous thromboembolism (VTE) compared with no use. Products that contain levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. ZOELY may have a risk of VTE in the same range as observed with CHC containing levonorgestrel. 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.
u2022 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 table below).
u2022 Epidemiological studies in women who use low dose (< 50 micrograms ethinylestradiol) CHC have found that out of 10 000 women, between 6 and 12 will develop a VTE in one year.
u2022 It is estimated that out of 10 000 women who use a levonorgestrel-containing CHC, about 6 will develop VTE in one year. This is based on a relative risk for CHCs containing levonorgestrel versus non-use of approximately 2,3 to 3,6.
u2022 The number of VTEs per year with low dose CHCs, such as ZOELY, is fewer than the number expected in women during pregnancy or in the postpartum period.
u2022 VTE may be fatal in 1 to 2 % of cases.
u2022 Thrombosis has also been reported to occur in the other blood vessels, e.g., hepatic, mesenteric, renal, cerebral or retinal veins and arteries, in users of CHCs such as ZOELY.
Risk factors for VTE
The risk for venous thromboembolic complications in users of CHCu2019s such as ZOELY, may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see table below). ZOELY 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 u2013 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: Risk factors for VTE
Risk factor Comment
Obesity (body mass index over 30 kg/mu00b2) Risk increases substantially as BMI rises. Particularly important to consider if other risk factors are 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 ZOELY has not been discontinued in advance (see section 4.3).
Positive family history (venous thromboembolism ever in a sibling or parent, especially at a relatively early age, e.g., before 50) 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, VTE 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 the 6-week period of the puerperium, must be considered (see section 4.6).
Symptoms of VTE (deep vein thrombosis and pulmonary embolism)
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, such as ZOELY. Symptoms of deep vein thrombosis (DVT) can include:
u2022 unilateral swelling of the leg and/or foot or along a vein in the leg;
u2022 pain or tenderness in the leg which may be felt only when standing or walking;
u2022 increased warmth in the affected leg; red or discoloured skin on the leg.
Symptoms of pulmonary embolism (PE) can include:
u2022 sudden onset of unexplained shortness of breath or rapid breathing;
u2022 sudden coughing which may be associated with haemoptysis;
u2022 sharp chest pain;
u2022 severe light headedness or dizziness;
u2022 rapid or irregular heartbeat.
Some of these symptoms (e.g., u2018shortness of breathu2019, u2018coughingu2019) 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 arterial thromboembolism (ATE)
Epidemiological studies have associated the use of CHCs, such as ZOELY, with an increased risk for arterial thromboembolism (myocardial infarction) or for cerebrovascular accident (e.g., transient ischaemic attack, 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 below). ZOELY 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 u2013 in this case her total risk should be considered. If the balance of benefits and risks is considered to be negative a CHC such as ZOELY should not be prescribed (see section 4.3).

Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.
Influence of other medicines on ZOELY
Interactions between ZOELY and other medicines may lead to breakthrough bleeding and/or contraceptive failure. The following interactions have been reported in the literature for COCs in general:
Hepatic metabolism: Interactions can occur with medicines or herbal products that induce cytochrome P450 enzymes (CYP) which can result in increased clearance reducing plasma concentrations of sex hormones and may decrease the effectiveness of combined oral contraceptives, including ZOELY. These products include anticonvulsants (e.g., carbamazepine, topiramate, phenytoin, phenobarbital, primidone, oxcarbazepine, felbamate); anti-infective medicines (e.g., rifampicin, rifabutin, griseofulvin); St. Johnu2019s wort; bosentan and HIV or Hepatitis C virus (HCV) protease inhibitors (e.g., ritonavir, nelfinavir boceprevir, telaprevir) and non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine, efavirenz). The net effect of these changes may be clinically relevant in some cases. Enzyme induction can occur after a few days of treatment. Maximal enzyme induction is generally observed within a few weeks. After medicine therapy is discontinued, enzyme induction can last for about 28 days.
Women receiving any of the above-mentioned hepatic enzyme-inducing medicines or herbal products should be advised that the efficacy of ZOELY may be reduced. A barrier contraceptive method should also be used during administration of the hepatic enzyme-inducing medicine, and for 28 days after discontinuation of the hepatic enzyme-inducing medicines. If concomitant medicine 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. For women on long-term therapy with hepatic enzyme-inducing medicines, an alternative method of contraception unaffected by enzyme-inducing medicines should be considered.
Concomitant administration of strong (e.g., ketoconazole, itraconazole, clarithromycin) or moderate (e.g., fluconazole, diltiazem, erythromycin) CYP3A inhibitors may increase the serum concentrations of estrogens or progestins.
Interaction studies were not performed with ZOELY, but 2 studies with rifampicin and ketoconazole, respectively, were performed with a higher dosed nomegestrol acetate-estradiol combination (nomegestrol acetate 3,75 mg + 1,5 mg estradiol) in post-menopausal women. Concomitant use of rifampicin decreases the AUC 0-u221e of nomegestrol acetate by 95 % and increases the AUC 0-tlast of estradiol by 25 %. Concomitant use of ketoconazole (200 mg single dose) does not modify estradiol metabolism whereas increases in the peak concentration (85 %) and AUC 0-u221e (115 %) of nomegestrol acetate were observed, which were of no clinical relevance. Similar conclusions are expected in women of childbearing potential. Women using rifamycins such as rifampicin, rifabutin and rifapentine should use additional contraceptive measures.
Influence of ZOELY on other medicines
ZOELY may affect the metabolism of other medicines. Accordingly, plasma and tissue concentrations may either increase (e.g., ciclosporin) or decrease (e.g., lamotrigine). Contraceptives containing ethinylestradiol, such as ZOELY, may decrease the concentrations of lamotrigine by approximately 50 %. Attention should be paid, notably when introducing a combined contraceptive, even with estradiol, in a well-equilibrated woman given lamotrigine.
Other interactions
Direct acting antiviral agents (DAAs) and ethinylestradiol-containing medicinal products such as CHCs During clinical trials with the Hepatitis C virus (HCV) combination medicine regimen ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medications 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. Direct acting antiviral agents (DAAs) and medicinal products containing oestrogens other than ethinylestradiol, such as estradiol Women using medicines containing estrogens other than ethinylestradiol, such as estradiol, and ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin had a rate of ALT elevation similar to those not receiving any estrogens. Caution is warranted for co-administration with the following combination medicine regimens ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section 4.4).

Pregnancy
ZOELY is not indicated during pregnancy (see section 4.3). If pregnancy occurs during treatment with ZOELY, further intake should be stopped. The increased risk of VTE during the postpartum period should be considered when re-starting ZOELY (see sections 4.2 and 4.4).
Lactation
ZOELY should not be used until the breastfeeding mother has completely weaned her child. An alternative contraceptive method should be proposed to women wishing to breastfeed. Lactation may be influenced by COCs such as ZOELY as they may reduce the quantity and change the composition of breast milk. Small amounts of the contraceptive steroids and/or their metabolites may be excreted with the milk.
Fertility
ZOELY is indicated for the prevention of pregnancy.

ZOELY has no influence on the ability to drive and use machines.

a. Summary of the safety profile
Seven multi-centre clinical trials of up to 2 years duration were used to evaluate safety of ZOELY. In total 3 490 women, aged 18 to 50, were enrolled and completed 35 028 cycles. An increased risk for venous and arterial thromboembolism, causative of serious adverse events, has been observed with the use of CHCs (see section 4.4)
b. Tabulated list of adverse reactions
Possibly related undesirable effects that have been reported in users of ZOELY are listed in the table below. All adverse reactions are listed by system organ class and frequency: Very common (u2265 1/10), Common (u2265 1/100 to < 1/10), Uncommon (u2265 1/1 000 to < 1/100) and Rare (u2265 1/10 000) to < 1/1 000).
Adverse Reactions in MedDRA Term 1
Body system Very common (u2265 1/10) Common (u2265 1/100 to < 1/10) Uncommon (u2265 1/1 000 to < 1/100) Rare (u2265 1/10 000) to < 1/1 000)
Metabolism and nutrition disorders Increased appetite, fluid retention Decreased appetite
Psychiatric disorders Decreased libido, depression/ depressed mood, mood altered Increased libido
Nervous system disorders Headache, migraine Cerebrovascular accident, transient ischaemic attack, disturbance in attention
Eye disorders Dry eye, contact lens intolerance
Vascular disorders Hot flushes Venous thromboembolism
Gastrointestinal disorders Nausea Abdominal distension Dry mouth
Hepatobiliary disorders Cholelithiasis, cholecystitis
Skin and subcutaneous tissue disorders Acne 2 Hyperhidrosis, alopecia, pruritus, dry skin, seborrhoea Chloasma, hypertrichosis
Musculoskeletal and connective tissue disorders Sensation of heaviness
Reproductive system and breast disorders Abnormal withdrawal bleeding Metrorrhagia, menorrhagia, breast pain, pelvic pain Hypomenorrhea, breast swelling, galactorrhoea, uterine spasm, premenstrual syndrome, breast mass, dyspareunia, vulvovaginal dryness Vaginal odour, vulvovaginal discomfort
General disorders and administrative site conditions Irritability, oedema Hunger
Investigations Increased weight Increased hepatic enzyme
1 The most appropriate MedDRA term to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed, but should be taken into account as well.
2 Acne was a solicited rather than spontaneously reported event, being assessed at every study visit.
c. Description of selected adverse reactions
Vascular disorders An increased risk of arterial and venous thrombotic and thromboembolic events, including myocardial infarction, stroke, transient ischaemic attacks, venous thrombosis and pulmonary embolism has been observed in women using CHCs such as ZOELY, which are discussed in more detail in section 4.4.
Immune system disorders Hypersensitivity reactions (anaphylactic shock, angioedema, dyspnoea, eyelid oedema, erythema, gingival swelling, lip swelling, paraesthesia, oral rash, swollen tongue and urticaria) have been reported in ZOELY users (frequency unknown).
Post-marketing reported side effects
The following side effects have been reported with post-marketing use of estrogen and/or progesterone/progestogen-containing medicines: Severe depression with a higher risk of suicidal thoughts/behaviours and suicide.

Multiple doses up to 5 times the daily dose of ZOELY and single doses up to 40 times the daily dose of nomegestrol acetate alone have been used in women without safety concern. On the basis of general experience with combined oral contraceptives, symptoms that may occur are nausea, vomiting and, in young girls, slight vaginal bleeding (see section 4.8). There are no antidotes and treatment should be symptomatic.