Zoely

Zoely

Manufacturer:

MSD

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Nomegestrol acetate, estradiol hemihydrate.
Description
White active film-coated tablets: Each film-coated tablet contains 2.5 mg nomegestrol acetate and 1.5 mg estradiol (as hemihydrate).
Yellow placebo film-coated tablets: The tablet does not contain active substances.
Excipient/Inactive Ingredients: Each white active film-coated tablet contains 57.71 mg of lactose monohydrate.
Each yellow placebo film-coated tablet contains 61.76 mg of lactose monohydrate.
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 coating (white active film-coated tablets): Poly(vinyl alcohol) (E1203), Titanium dioxide (E171), Macrogol 3350, Talc (E553b).
Tablet coating (yellow placebo film-coated tablets): Poly(vinyl alcohol) (E1203), Titanium dioxide (E171), Macrogol 3350, Talc (E553b), Ferric oxide yellow (E172), Ferric oxide black (E172).
Action
Pharmacotherapeutic group: Sex hormones and modulators of the genital system, progestogens and estrogens, fixed combinations. ATC code: G03AA14.
Pharmacology: Pharmacodynamics: Nomegestrol acetate is a highly selective progestagen derived from the naturally occurring steroid hormone, progesterone. Nomegestrol acetate has a strong affinity for the human progesterone receptor and has an anti-gonadotropic activity, a progesterone receptor-mediated anti-estrogenic activity, a moderate anti-androgenic activity, and is devoid of any estrogenic, androgenic, glucocorticoid or mineralocorticoid activity.
The estrogen contained in Zoely is 17β-estradiol, a natural estrogen identical to the endogenous human 17β-estradiol (E2). This estrogen differs from the estrogen ethinylestradiol used in other COCs by the lack of the ethinyl group in the 17alpha position. During use of Zoely, the average E2 levels are comparable to the E2 levels during the early follicular and late luteal phase of the menstrual cycle (see Pharmacokinetics as follows).
The contraceptive effect of Zoely is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation and the changes in the cervical secretion.
In two randomized, open-label, comparative efficacy-safety trials, more than 3,200 women, age 18-50 years, were treated for up to 13 consecutive cycles with Zoely and more than 1,000 women with drospirenone 3 mg - ethinylestradiol 30 μg (21/7 regimen).
In the Zoely group, weight increased was reported by 8.6% of the women (versus 5.7% in the comparator group), abnormal withdrawal bleeding (predominantly absence of withdrawal bleeding) was reported by 10.5% of the women (versus 0.5% in the comparator group), and acne was reported by 15.4% of the women (versus 7.9% in the comparator group) (see Adverse Reactions). Acne assessments during Zoely treatment showed that most women (73.1%) had no change in acne status as compared to pre-treatment while 16.8% had improvement of acne and 10.1% had new or worsening of acne.
In the clinical trial performed with Zoely in the European Union, Asia, and Australia, the following Pearl Indices for the age 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, Canada, and Latin America, the following Pearl Indices for the age class 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 randomized, open label trial, 32 women were treated for 6 cycles with Zoely.
After discontinuation of Zoely, return to ovulation occurred on average at 20.8 days after the last tablet intake, with the earliest ovulations detected at 16 days.
Folic acid is an important vitamin in the early phase of pregnancy. Folic acid serum levels remained unchanged during and after Zoely treatment for 6 consecutive cycles as compared to baseline.
In a randomized, open label, 2 year comparative trial, women 21-35 years of age, were treated with Zoely without a clinically relevant effect on bone mineral density.
A randomized, open-label, comparative, multicenter trial was performed to assess effects of Zoely on hemostasis, lipids, carbohydrate metabolism, adrenal and thyroid function and on androgens. Sixty women, 18-50 years of age, were treated with Zoely for 6 consecutive cycles. Glucose tolerance and insulin sensitivity remained unaltered and no clinically relevant effects on lipid metabolism and hemostasis were observed with Zoely. Zoely increased the carrier proteins TBG and CBG and induced a small increase in SHBG. The androgenic parameters androstenedione, DHEA-S, total and free testosterone were significantly reduced during use of Zoely.
Endometrial histology was investigated in a subgroup of women (n=32) in one clinical study after 13 cycles of treatment. There were no abnormal results.
Paediatric population: No data on efficacy and safety are available in adolescents below 18 years. Available pharmacokinetic data are described in Pharmacokinetics as follows.
Pharmacokinetics: Nomegestrol acetate (NOMAC): Absorption: Orally administered nomegestrol acetate is rapidly absorbed.
Maximum plasma concentrations of nomegestrol acetate of about 7 ng/ml are reached at 2 h after single 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.
Distribution: Nomegestrol acetate is extensively bound to albumin (97-98 %), but does not bind to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG). The apparent volume of distribution of nomegestrol acetate at steady-state is 1,645 ± 576 l.
Biotransformation: Nomegestrol acetate is metabolized into several inactive hydroxylated metabolites by liver cytochrome P450 enzymes, mainly CYP3A4 and CYP3A5 with possible contribution of CYP2C19 and CYP2C8. Nomegestrol acetate and its hydroxylated metabolites undergo extensive phase 2 metabolism to form glucuronide- and sulphate conjugates. The apparent clearance at steady state is 26 l/h.
Elimination: The elimination half-life (t1/2) is 46 h (ranging from 28-83 h) at steady state. The elimination half-life of metabolites was not determined.
Nomegestrol acetate is excreted via urine and feces. Approximately 80 % of the dose is excreted in urine and feces within 4 days. Excretion of nomegestrol acetate was nearly complete after 10 days and amounts excreted were higher in feces than in urine.
Linearity: Dose-linearity was observed in the range 0.625-5 mg (assessed in fertile and post-menopausal women).
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 about 12 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 P450 enzymes and has no clinically relevant interaction with the P-gp transporter.
Estradiol (E2): Absorption: Estradiol is subject to a substantial first-pass effect after oral administration. The absolute bioavailability is about 1%. No clinically relevant effect of food was observed on the bioavailability of estradiol.
Distribution: The distribution of exogenous and endogenous estradiol is similar. Estrogens are widely distributed in 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 only approximately 1-2% is unbound.
Biotransformation: Oral exogenous estradiol is extensively metabolized. The metabolism of exogenous and endogenous estradiol 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 a dynamic equilibrium between estradiol, estrone and estrone-Sulfate due to various enzymatic activities including estradiol-dehydrogenases, sulfotransferases and aryl sulfatases. Oxidation of estrone and estradiol involves cytochrome P450 enzymes, mainly CYP1A2, CYP1A2 (extra hepatic), CYP3A4, CYP3A5, and CYP1B1 and CYP2C9.
Elimination: Estradiol is rapidly cleared from the circulation. Due to metabolism and enterohepatic circulation, a large circulating pool of estrogen sulfates and glucuronides is present. This results in a highly variable baseline-corrected elimination half-life of estradiol, which is calculated to be 3.6±1.5 h, after intravenous 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 and late phase of a woman's menstrual cycle.
Special Populations: Paediatric population: The pharmacokinetics of nomegestrol acetate (primary objective) after single oral dosing of Zoely in healthy postmenarcheal female adolescents and adult subjects were similar. The exposure of estradiol (secondary objective) was similar in adolescents versus adult subjects during the first 24 hours, and lower after 24 hours. The clinical relevance of this result is unknown.
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.
Toxicology: Preclinical safety data: Repeat dose toxicity studies with estradiol, nomegestrol acetate or combination have indicated expected estrogenic and gestagen effects.
Reproductive toxicity studies performed with the combination have shown foetotoxicity which is consistent with estradiol exposure.
Genotoxicity and carcinogenicity studies were not conducted with the combination. Nomegestrol acetate is not genotoxic.
However, it must be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumours.
Indications/Uses
Oral contraception.
Dosage/Direction for Use
Posology: 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 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 2-3 after intake of the last white tablet and may not have finished before the next pack is started. See Cycle control under Precautions.
Special populations: Renal impairment: Although data in renal impaired patients are not available, renal impairment is unlikely to affect the elimination of nomegestrol acetate and estradiol.
Hepatic impairment: No clinical studies have been performed in patients with hepatic insufficiency. Since the metabolism of steroid hormones might be impaired in patients with severe hepatic disease, the use of Zoely in these women is not indicated as long as liver function values have not returned to normal (see Contraindications).
Method of administration: Oral use.
How to take Zoely: Tablets must be taken every day at about the same time without regard to meals. Tablets should be taken with some liquid as needed, and in the order as directed on the blister. Stickers marked with the 7 days of the week are provided. The woman should choose the sticker that starts with the day she begins 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 natural cycle (i.e. the first day of her menstrual bleeding). When doing so, no additional contraceptive measures are necessary. Starting on days 2-5 is allowed, but during the first pill pack a barrier method should be used until the woman has completed 7 days of uninterrupted white tablet taking.
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 active tablet (the last tablet containing the active substances) of her previous COC, but at the latest on the day following the usual tablet-free or placebo tablet interval of her previous COC. In case a vaginal ring or transdermal patch has been used, the woman should start using Zoely preferably on the day of removal, but at the latest when the next application would have been due.
Changing from a progestogen-only-method (minipill, implant, injectable) or from a hormone medicated Intra Uterine System (IUS): The woman may switch any day from the minipill and Zoely should be started on the next day. An implant or IUS may be removed 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 immediately. When doing so, no additional contraceptive measures are necessary.
Following delivery or second-trimester abortion: 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 until she has completed 7 days of uninterrupted white active tablet-taking. However, if intercourse has already occurred, pregnancy should be excluded before the actual start of COC use or the woman has to wait for her first menstrual period.
For breast-feeding women see Use in Pregnancy & Lactation.
The increased risk of VTE during the postpartum period should be considered when restarting Zoely (see Precautions).
Management of missed tablets: The following advice only refers to missed white active tablets: If the 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 further 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: 7 days of uninterrupted 'white active tablet'-taking are required to attain adequate suppression of the hypothalamic-pituitary-ovarian-axis.
The more 'white active tablets' are missed and the closer the missed tablets are to the 4 yellow placebo tablets, the higher the risk of a pregnancy.
Day 1-7: The user should take the last missed white 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. In addition, a barrier method such as a condom 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 8-17: The user should take the last missed white 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.
Provided that the woman has taken her tablets correctly in the 7 days preceding the first missed tablet, there is no need to use extra contraceptive precautions. However, if she has missed more than 1 tablet, the woman should be advised to use extra precautions until she has completed 7 days of uninterrupted white tablet-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 be prevented. By adhering to either of the following two options, there is therefore no need to use extra 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 extra precautions for the next 7 days as well.
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 tablet-taking days.
The woman may also be advised to discontinue active tablet-taking 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 color of tablets missed and what advice to follow, a barrier 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 gastro-intestinal disturbances: In case of severe gastro-intestinal disturbance (e.g., vomiting or diarrhoea), absorption of the active substances 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 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 in Management of missed tablets, 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 placebo tablets from her current pack. The extension can be carried on for as long as wished until the end of the white active tablets in the second pack. Regular intake of Zoely is then resumed after the yellow placebo tablets have been taken of the second pack. During the extension the woman may 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, she can be advised to shorten her forthcoming yellow placebo tablet phase with 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).
Overdosage
Multiple doses up to five 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. There are no antidotes and further treatment should be symptomatic.
Contraindications
Combined hormonal contraceptives (CHCs) should not be used in the presence of any of the conditions listed as follows. As no epidemiological data are yet available with 17β-estradiol-containing combined oral contraceptives (COCs), the contraindications for ethinylestradiol-containing CHCs are considered applicable to the use of Zoely. Should any of the conditions appear for the first time during Zoely use, the medicinal product should be stopped immediately.
Hypersensitivity to the active substances or to any of the excipients of Zoely.
Presence or history of venous thrombosis (deep venous thrombosis, pulmonary embolism).
Presence or history of arterial thrombosis (e.g. myocardial infarction) or prodromal conditions (e.g. transient ischaemic attack, angina pectoris).
Presence or history of cerebrovascular accident.
History of migraine with focal neurological symptoms.
The presence of a severe or multiple risk factor(s) for venous or arterial thrombosis (see Precautions) such as: diabetes mellitus with vascular symptoms; severe hypertension; severe dyslipoproteinemia.
Major surgery with prolonged immobilisation (see Precautions).
Hereditary or acquired predisposition for venous or arterial thrombosis, such as activated protein C (APC) resistance, antithrombin-III-deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinaemia and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).
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 returned to normal.
Presence or history of liver tumours (benign or malignant).
Known or suspected sex steroid-influenced malignancies (e.g., of the genital organs or the breasts).
Known or suspected pregnancy.
Warnings
Contraindicated in patients who have blood clot in blood vessel and liver disease.
Should not use in women who have risk of blood clot in blood vessel e.g. have history of angiitis, obesity, diabetes and hypertension.
Not recommended in patients with liver tumours or patients who have history of liver tumours and patients or suspected patients who have sex hormone related cancer such as breast cancer or reproductive organ cancer.
Use with caution in smoking women especially women older than 35 years should consult doctor before use.
Seek medical consultation in case of use other than for contraception.
Consult doctor if the patient notices disorder symptom.
Special Precautions
Warnings: If any of the conditions/risk factors mentioned as follows is present, the benefits of the use of Zoely should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start using Zoely. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the woman should contact her physician. The physician should then decide on whether the use of Zoely should be discontinued. All data presented as follows are based upon epidemiological data obtained with COCs containing ethinylestradiol. Zoely contains 17β estradiol. As no epidemiological data are yet available with 17β-estradiol-containing COCs, the warnings are considered applicable to the use of Zoely.
Circulatory Disorders: The following data are based upon epidemiological data obtained with CHCs containing ethinylestradiol. Zoely contains 17β-estradiol. As no epidemiological data are yet available with 17β-estradiol-containing COCs, the warnings are considered applicable to the use of Zoely.
The use of CHCs carries an increased risk of venous thromboembolism (VTE) compared with no use. The excess risk of VTE is highest during the first year a woman ever uses a CHC. The risk is also increased after initially starting a CHC or restarting the same or different CHC after a break in use of 4 weeks or more.
Epidemiological studies have shown that the incidence of VTE in women with no known risk factors for VTE who use low dose oestrogen (<50 μg ethinylestradiol) CHCs ranges from about 3 to 12 cases per 10,000 women-years. This compares with 1 to 5 cases per 10,000 women-years for non-users and 5 to 20 cases per 10,000 women-years for pregnant women. VTE is fatal in 1-2% of cases.
The figure as follows shows the risk of developing a VTE for women who are not pregnant and do not use CHCs, for women who use CHCs, for pregnant women, and for women in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 women who are not pregnant and do not use CHCs are followed for one year, between 1 and 5 of these women will develop a VTE. (See figure.)

Click on icon to see table/diagram/image

It is not known how Zoely influences this risk compared with other CHCs.
Epidemiological studies have also associated the use of CHCs with an increased risk for arterial thromboembolism (myocardial infarction, transient ischaemic attack).
Extremely rarely, thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral or retinal veins and arteries, in CHC users.
Symptoms of venous or arterial thrombosis or of a cerebrovascular accident can include: unusual unilateral leg pain and / or swelling; sudden severe pain in the chest, whether or not it radiates to the left arm; sudden breathlessness; sudden onset of coughing; any unusual, severe, prolonged headache; sudden partial or complete loss of vision; diplopia; slurred speech or aphasia; vertigo; collapse with or without focal seizure; weakness or very marked numbness suddenly affecting one side or one part of the body; motor disturbances; 'acute' abdomen.
The risk of venous thromboembolic events increases with: increasing age; a positive family history (i.e. venous thromboembolism ever in a sibling or parent at a relatively early age). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any hormonal contraceptive use; prolonged immobilisation, major surgery, any surgery to the legs, or major trauma. In these situations it is advisable to discontinue use (in the case of elective surgery at least four weeks in advance) and not to resume until two weeks after complete remobilisation. Antithrombotic treatment should be considered if COC use has not been discontinued in advance. See also Contraindications; obesity (body mass index over 30 kg/m2).
There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in the onset of venous thrombosis.
The risk of arterial thromboembolic complications or of a cerebrovascular accident increases with: increasing age; smoking (with heavier smoking and increasing age the risk further increases, especially in women over 35 years of age. Women over 35 years of age should be strongly advised not to smoke if they wish to use a COC); dyslipoproteinemia; obesity (body mass index over 30 kg/m2); hypertension; migraine; valvular heart disease; atrial fibrillation; a positive family history (arterial thrombosis ever in a sibling or parent at a relatively early age). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any hormonal contraceptive use.
Other medical conditions, which have been associated with adverse circulatory events, include diabetes mellitus, systemic lupus erythematosus, hemolytic uraemic syndrome, chronic inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis) and sickle cell disease.
The increased risk of thromboembolism in the puerperium must be considered (see Use in Pregnancy & Lactation).
An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of Zoely use.
Women using COCs should be specifically pointed out to contact their physician in case of possible symptoms of thrombosis. In case of suspected or confirmed thrombosis, COC use should be discontinued. Adequate contraception should be initiated because of the teratogenicity of anti-coagulant therapy (coumarins).
Tumours: All data presented as follows are based upon epidemiological data obtained with COCs containing ethinylestradiol. Zoely contains 17β-estradiol. As no epidemiological data are yet available with 17β-estradiol-containing COCs, the warnings are considered applicable to the use of Zoely.
The most important risk factor for cervical cancer is persistent human papilloma virus (HPV) infection. Epidemiological studies have indicated that long-term use of ethinylestradiol-containing COCs contributes to this increased risk, but there continues to be uncertainty about the extent to which this finding is attributable to confounding effects, like increased cervical screening and difference in sexual behavior including use of barrier contraceptives, or a causal association.
With the use of the higher-dosed COCs (50 μg ethinylestradiol) the risk of endometrial and ovarian cancer is reduced. Whether this also applies to 17β-estradiol-containing COCs 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 ethinylestradiol-containing 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 of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.
In another epidemiological study of 1.8 million Danish women followed an average of 10.9 years, the reported RR of breast cancer among COC users increased with longer duration of use compared with women who never used COCs (overall RR = 1.19; RR ranged from 1.17 for 1 to less than 5 years of use to 1.46 after more than 10 years of use). The reported absolute risk difference (number of breast cancer cases between never-users compared with current and recent COC users) was small: 13 per 100,000 woman-years.
Epidemiological studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both.
In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been reported in users of COCs. In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhages. Therefore, a hepatic tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage occur in women taking COCs.
Hepatitis C: During clinical trials with the Hepatitis C virus (HCV) combination drug regimen ombitasvir/paritaprevir/ritonavir with and without dasabuvir, 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. Women using medications containing estrogens other than ethinylestradiol, such as estradiol had a rate of ALT elevation similar to those not receiving any estrogens; however, due to the limited number of women taking these other estrogens, caution is warranted for co-administration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir. See Interactions.
Other conditions: All data presented as follows are based upon epidemiological data obtained with COCs containing ethinylestradiol. Zoely contains 17β-estradiol. As no epidemiological data are yet available with 17β-estradiol-containing COCs, the warnings are considered applicable to the use of Zoely.
Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis 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 hypertension has not been established. However, if a sustained clinically significant hypertension develops during the use of a COC then it is prudent for the physician to suspend the intake of the tablets and treat the hypertension. Where considered appropriate, COC use may be resumed if normotensive values can be achieved with antihypertensive therapy.
In seven multi-center clinical trials of up to two years duration, no clinically relevant changes in blood pressure were observed with Zoely.
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/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham's chorea; herpes gestationis; otosclerosis-related hearing loss.
In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.
Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. Recurrence of cholestatic jaundice which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of COCs.
Although COCs may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics using low-dose COCs (containing < 0.05 mg ethinylestradiol). However, diabetic women should be carefully observed while taking a COC especially in the first months of use. Zoely was shown to have no effect on peripheral insulin resistance and glucose tolerance in healthy women (see Pharmacology: Pharmacodynamics under Actions).
Crohn's disease, ulcerative colitis, and worsening of depression have been associated with COC use.
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking COCs.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Medical Examination/Consultation: Prior to the initiation or reinstitution of Zoely use a complete medical history (including family history) should be taken and pregnancy must be ruled out. Blood pressure should be measured and if clinically indicated a physical examination should be performed, guided by the contra-indications (see Contraindications) and warnings (see previous text). The woman should also be instructed to carefully read the user leaflet and to adhere to the advice given. The frequency and nature of further periodic checks should be based on established practice guidelines and be adapted to the individual woman.
Women should be advised that oral contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.
Reduced efficacy: The efficacy of COCs may be reduced in the event of e.g., missed tablets (see Dosage & Administration), gastro-intestinal disturbances during active tablet taking (see Dosage & Administration) or use of concomitant medicinal products that decrease the plasma concentrations of nomegestrol acetate (see Interactions).
Cycle control: With all COCs, breakthrough bleeding or spotting may occur, especially during the first months of use. Therefore, the evaluation of any breakthrough bleeding or spotting is only meaningful after an adaptation interval of about 3 cycles. The percentage of women using Zoely experiencing intracyclic bleeding after this adaptation period ranged from 15-20 %. If bleeding irregularities persist or occur after previously regular cycles, then non-hormonal causes should be considered and adequate diagnostic measures are indicated to exclude malignancy or pregnancy. These may include curettage.
The duration of withdrawal bleeding in women using Zoely is on average 3-4 days. Users of Zoely may also miss their withdrawal bleeding although not pregnant. During clinical trials, absence of withdrawal bleeding ranged from 18% to 32% (over cycles 1-12). In such cases, absence of withdrawal bleeding was not associated with a higher occurrence of breakthrough bleeding/spotting in subsequent cycles. 4.6% of the women experienced absence of withdrawal bleeding in each of the first three cycles of use. Within this subgroup, the percentage of women experiencing absence of withdrawal bleeding in later cycles was high, ranging from 76% to 87%. Of 28% of the women who experienced absence of withdrawal bleeding in at least one cycle (during cycles 2, 3 or 4), 51% to 62% of these women also experienced absence of withdrawal bleeding in later cycles.
If absence of withdrawal bleeding occurs and Zoely has been taken according to the instructions as described in Dosage & Administration, it is unlikely that the woman is pregnant. If Zoely has not been taken as directed or if two consecutive withdrawal bleedings are missed, pregnancy must be ruled out before Zoely is continued.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed with Zoely. However, no effects on ability to drive and use machines have been observed in users of COCs.
Fertility: Zoely is indicated for the prevention of pregnancy. For information on return to fertility, see Pharmacology: Pharmacodynamics under Actions.
Use in Children: It is unknown whether the amount of estradiol in Zoely is sufficient to maintain adequate levels of estradiol in adolescents, especially for bone mass accrual (see Pharmacology: Pharmacokinetics under Actions).
Use In Pregnancy & Lactation
Pregnancy: Zoely is not indicated during pregnancy.
If pregnancy occurs while taking Zoely, further intake should be stopped. Most epidemiological studies have revealed neither an increased risk of birth defects in infants born to women who used ethinylestradiol-containing COCs prior to pregnancy, nor a teratogenic effect when ethinylestradiol-containing COCs were taken inadvertently during early pregnancy. Clinical data on a limited number of exposed pregnancies indicate no adverse effect of Zoely on the foetus or neonate.
In animal studies, reproductive toxicity has been observed with the nomegestrol acetate / estradiol combination (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Breastfeeding: Lactation may be influenced by COCs as they may reduce the quantity and change the composition of breast milk. Therefore, the use of COCs should not be recommended until the nursing mother has completely weaned her child and an alternative contraceptive method should be proposed to women wishing to breastfeed. Small amounts of the contraceptive steroids and/or their metabolites may be excreted with the milk, but there is no evidence that this adversely affects infant health.
Adverse Reactions
Summary of the safety profile: Seven multi-center clinical trials of up to two years duration were used to evaluate safety of Zoely. In total 3,490 women, aged 18-50, were enrolled and completed 35,028 cycles.
Tabulated summary of adverse reactions: Possibly related adverse reactions that have been reported in users of Zoely are listed in the table as follows.
All adverse reactions are listed by system organ class and frequency; 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). (See table.)

Click on icon to see table/diagram/image

In addition to the previously mentioned adverse reactions, venous thromboembolism, arterial thromboembolism, and hypersensitivity reactions have been reported in Zoely users (frequency unknown).
Description of selected adverse reactions: A number of adverse reactions have been reported in women using combined oral contraceptives containing ethinylestradiol, which are discussed in more detail in Precautions.
Drug Interactions
Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.
Influence of other medicinal products on Zoely: Interactions between oral contraceptives and enzyme-inducing medicinal products may lead to breakthrough bleeding and even contraceptive failure.
Hepatic metabolism: Interactions can occur with medicinal or herbal products that induce microsomal enzymes, specifically 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 phenytoin, phenobarbital, primidone, bosentan, carbamazepine, rifampicin, and medicinal products or herbal preparations containing St. John's wort, and, to a lesser extent, oxcarbazepine, topiramate, felbamate, griseofulvin, and some HIV protease inhibitors (e.g. ritonavir and nelfinavir) and non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine and efavirenz).
Enzyme induction can occur after a few days of treatment. Maximal enzyme induction is generally observed within a few weeks. After drug therapy is discontinued, enzyme induction can last for about 28 days.
When co-administered with hormonal contraceptives, many combinations of HIV protease inhibitors (e.g. nelfinavir) and non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine), and/or combinations with Hepatitis C virus (HCV) medicinal products (e.g., boceprevir, telaprevir), can increase or decrease plasma concentrations of progestins, including nomegestrol acetate, or estrogen. The net effect of these changes may be clinically relevant in some cases.
Women receiving any of the above-mentioned hepatic enzyme-inducing medicinal 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 medicinal product, and for 28 days after discontinuation of the hepatic enzyme-inducing medicinal product. 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. For women on long-term therapy with hepatic enzyme-inducing medicinal products, an alternative method of contraception unaffected by enzyme-inducing medicinal products 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. Medicinal product interaction studies were not performed with Zoely, but two 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 AUC0-∞ of nomegestrol acetate by 95% and increases the AUC0-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 AUC0-∞ (115%) of nomegestrol acetate were observed, which were of no clinical relevance. Similar conclusions are expected in women of childbearing potential.
Influence of Zoely on other medicinal products: Oral contraceptives may affect the metabolism of other medicinal products. Accordingly, plasma and tissue concentrations may either increase (e.g. ciclosporin) or decrease (e.g. lamotrigine).
Other interactions: During clinical trials with the HCV combination drug regimen ombitasvir/paritaprevir/ritonavir with and without dasabuvir, 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. Women using medications containing estrogens other than ethinylestradiol, such as estradiol had a rate of ALT elevation similar to those not receiving any estrogens; however, due to the limited number of women taking these other estrogens, caution is warranted for co-administration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir.
Laboratory tests: The use of COCs may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins, e.g., corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.
Caution For Usage
Special Precautions for Disposal: COC tablets (including Zoely tablets) no longer required should not be disposed via wastewater or the municipal sewage system. The hormonal active compounds in the tablet may have harmful effects if reaching the aquatic environment. The tablets should be returned to a pharmacy or disposed of in another safe way according to local requirements. These measures will help to protect the environment.
Incompatibilities: Not applicable.
Storage
Store at 2°C to 30°C.
Shelf life: 36 months.
MIMS Class
ATC Classification
G03AA14 - nomegestrol and estradiol ; Belongs to the class of progestogens and estrogens in fixed combinations. Used as systemic contraceptives.
Presentation/Packing
FC tab (white, round and coded 'ne' on both sides) 28's.
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