Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Theramex Ireland Limited, 3rd Floor, Kilmore House, Park Lane, Spencer Dock, Dublin 1, D01 YE64, Ireland
CHCs must not be used in the following conditions. Should any of the conditions appear for the first
time during Zoely use, the medicinal product should be stopped immediately.
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 doctor to determine whether the use of Zoely should be discontinued. All data presented below are based upon epidemiological data obtained with CHCs containing ethinylestradioland apply to Zoely.
The risk for venous thromboembolic complications in CHC users may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see table).
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 – 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/m²) | Risk increases substantially as BMI rises. Particularly important to consider if other risk factors also present. |
| Prolonged immobilisation, major surgery, any surgery to the legs or pelvis, neurosurgery, or major trauma Note: Temporary immobilisation including air travel >4 hours can also be a risk factor for VTE, particularly in women with other risk factors. | In these situations it is advisable to discontinue use of the pill (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation. Another method of contraception should be used to avoid unintentional pregnancy. Antithrombotic treatment should be considered if Zoely has not been discontinued in advance. |
| 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, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis) and sickle cell disease |
| Increasing age | Particularly above 35 years |
In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.
Symptoms of deep vein thrombosis (DVT) can include:
Symptoms of pulmonary embolism (PE) can include:
Some of these symptoms (e.g. “shortness of breath”, “coughing”) are non-specific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections). Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of an extremity.
If the occlusion occurs in the eye symptoms can range from painless blurring of vision which can progress to loss of vision. Sometimes loss of vision can occur almost immediately.
Epidemiological studies have associated the use of CHCs 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.
The risk of arterial thromboembolic complications or of a cerebrovascular accident in CHC users increases in women with risk factors (see table). 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 – in this case her total risk should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed (see section 4.3).
Table. Risk factors for ATE:
| Risk factor | Comment |
|---|---|
| Increasing age | Particularly above 35 years |
| Smoking | Women should be advised not to smoke if they wish to use a CHC. Women over 35 who continue to smoke should be strongly advised to use a different method of contraception. |
| Hypertension | |
| Obesity (body mass index over 30 kg/m²) | Risk increases substantially as BMI increases. Particularly important in women with additional risk factors |
| Positive family history (arterial thromboembolism ever in a sibling or parent especially at relatively early age, e.g., below 50) | If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use. |
| Migraine | An increase in frequency or severity of migraine during CHC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation. |
| Other medical conditions associated with adverse vascular events | Diabetes mellitus, hyperhomocysteinaemia, valvular heart disease and atrial fibrillation, dyslipoproteinaemia and systemic lupus erythematosus |
In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.
Symptoms of a cerebrovascular accident can include:
Temporary symptoms suggest the event is a transient ischaemic attack (TIA).
Symptoms of a myocardial infarction (MI) can include:
The occurrence of meningiomas (single and multiple) has been reported in association with use of nomegestrol acetate, especially at high doses and for prolonged use (several years). Patients should be monitored for signs and symptoms of meningiomas in accordance with clinical practice. If a patient is diagnosed with meningioma, any nomegestrol acetate-containing treatment, must be stopped, as a precautionary measure.
There is some evidence that the meningioma risk may decrease after treatment discontinuation of nomegestrol acetate.
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 a physical examination should be performed, guided by the contraindications (see section 4.3) and warnings (see section 4.4). It is important to draw a woman’s attention to the information on venous and arterial thrombosis, including the risk of Zoely compared with other CHCs, the symptoms of VTE and ATE, the known risk factors and what to do in the event of a suspected thrombosis.
The woman should also be instructed to carefully read the user leaflet and to adhere to the advice given. The frequency and nature of examinations should be based on established practice guidelines and be adapted to the individual woman.
Women should be advised that hormonal contraceptives do not protect against human immunodeficiency virus (HIV) infections (which can cause acquired immunodeficiency syndrome [AIDS]) and other sexually transmitted diseases.
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 concomitant medicinal products that decrease the plasma concentrations of nomegestrol acetate and/or estradiol (see section 4.5).
With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. Therefore, the evaluation of any irregular bleeding is only meaningful after an adaptation interval of about 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 the withdrawal bleeding in women using Zoely is on average 3-4 days. Users of Zoely may also miss their withdrawal bleeding although not being pregnant. During clinical trials, absence of withdrawal bleeding ranged over the cycles 1-12 from 18% to 32%. In such cases, absence of withdrawal bleeding was not associated with a higher occurrence of breakthrough bleeding/spotting in the subsequent cycles. 4.6% of the women did not have a withdrawal bleeding in the first three cycles of use and the occurrences of absence of withdrawal bleeding in the later cycles of use were high in this subgroup, ranging from 76% to 87% of women. 28% of the women experienced absence of withdrawal bleeding in at least one of the cycles 2, 3 and 4, associated with higher occurrences of absence 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 as described in section 4.2, it is unlikely that the woman is pregnant. However, pregnancy must be ruled out before Zoely use is continued, if Zoely has not been taken as directed or if two consecutive withdrawal bleedings are missed.
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 section 5.2).
The use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins, e.g., corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Note: The prescribing information of concomitant medicinal products should be consulted to identify potential interactions.
Interactions between oral contraceptives and enzyme-inducing medicinal products may lead to breakthrough bleeding and/or contraceptive failure.
Hepatic metabolism: Interactions can occur with substances that induce CYP450 enzymes, resulting in reduced 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 transcriptase inhibitors (e.g. 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.
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-inducing substances 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 concentrations of oestrogens or progestogens.
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.
Contraceptives containing ethinylestradiol 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.
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 medicinal products such as CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co-administration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir and also 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 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 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 breast milk, 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 the composition of breast milk. Therefore, the use of COCs should not be recommended until the breastfeeding mother has completely weaned her child and an alternative method of contraception should be proposed to women wishing to breastfeed.
Zoely is indicated for the prevention of pregnancy. For information on return to fertility, see section 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 total 3,434 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 withdrawal bleeding irregular (9.8%).
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).
Possibly related adverse reactions that have been reported in clinical trials or during post-marketing use with Zoely are listed in the table below.
Adverse reactions are listed according to the MedDRA system organ class and ranked under frequency groupings 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:
| System organ class | Adverse reaction in MedDRA Term1 | |||
|---|---|---|---|---|
| Very common | Common | Uncommon | Rare | |
| 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 | contact lens intolerance/dry eye | |||
| Vascular disorders | hot flush | venous thromboembolism | ||
| Gastrointestinal disorders | nausea | abdominal distension | dry mouth | |
| Hepatobiliary disorders | cholelithiasis, cholecystitis | |||
| Skin and subcutaneous tissue disorders | acne | hyperhydrosis, alopecia, pruritus, dry skin, seborrhea | chloasma, hypertrichosis | |
| Musculoskeletal and connective tissue disorders | sensation of heaviness | |||
| Reproductive system and breast disorders | abnormal withdrawal bleeding | metrorrhagia, menorrhagia, breast pain, pelvic pain | hypomenorrhoea, breast swelling, galactorrhoea, uterine spasm, premenstrual syndrome, breast mass, dyspareunia, vulvovaginal dryness | vaginal odour, vulvovaginal discomfort |
| General disorders and administration site conditions | irritability, oedema | hunger | ||
| Investigations | weight increased | hepatic enzyme increased | ||
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.
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 myocardial infarction, stroke, transient ischaemic attacks, venous thrombosis and pulmonary embolism has been observed 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. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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