Special Warning : אזהרת שימוש

4.4        Special warnings and precautions for use

Warnings
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 ethinylestradiol and apply to Zoely.

Risk of venous thromboembolism (VTE)
•    The use of any combined hormonal contraceptive (CHC) increases the 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.
•    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 below).
•    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.
•    It is estimated that out of 10,000 women who use a levonorgestrel-containing CHC about 61 will develop a VTE in one year.
•    The number of VTEs per year with low dose CHCs is fewer than the number expected in women during pregnancy or in the postpartum period.
•    VTE may be fatal in 1-2 % of cases.
•    Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal, or retinal veins and arteries.

Risk factors for VTE
The risk for venous thromboembolic complications in CHC users may increase substantially in 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 
1
Mid-point of range of 5-7 per 10,000 WY, based on a relative risk for CHCs containing levonorgestrel versus non-use of approximately 2.3 to 3.6 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 In these situations, it is advisable to surgery to the legs or pelvis, neurosurgery, or discontinue use of the pill (in the case of major trauma                                    elective surgery at least four weeks in advance) and not resume until two weeks
Note: Temporary immobilisation including air after complete remobilisation. Another travel > 4 hours can also be a risk factor for  method of contraception should be used to VTE, particularly in women with other risk      avoid unintentional pregnancy.
factors.
Antithrombotic treatment should be considered if Zoely has not been discontinued in advance.

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

Other medical conditions associated with           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 pregnancy, and particularly the 6-week period of the puerperium, must be considered (for information on "Pregnancy and lactation" 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.
Symptoms of deep vein thrombosis (DVT) can include:
- unilateral swelling of the leg and/or foot or along a vein in the leg; - pain or tenderness in the leg which may be felt only when standing or walking; - increased warmth in the affected leg; red or discoloured skin on the leg.

Symptoms of pulmonary embolism (PE) can include:
- sudden onset of unexplained shortness of breath or rapid breathing; - sudden coughing which may be associated with haemoptysis;
- sharp chest pain;
- severe light headedness or dizziness;
- rapid or irregular heartbeat.
Some of these symptoms (e.g. “shortness of breath”, “coughing”) are non-specific and might 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 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). 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                     If a hereditary predisposition is suspected, thromboembolism ever in a sibling or parent           the woman should be referred to a specialist especially at relatively early age, e.g., below       for advice before deciding about any CHC 50)                                                   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              Diabetes mellitus, hyperhomocysteinaemia, adverse vascular events                               valvular heart disease and atrial fibrillation, dyslipoproteinaemia and systemic lupus erythematosus


Symptoms of ATE
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:
- sudden numbness or weakness of the face, arm or leg, especially on one side of the body;
- sudden trouble walking, dizziness, loss of balance or coordination; - sudden confusion, trouble speaking or understanding;
- sudden trouble seeing in one or both eyes;
- sudden, severe or prolonged headache with no known cause;
- loss of consciousness or fainting with or without seizure.

Temporary symptoms suggest the event is a transient ischaemic attack (TIA).

Symptoms of a myocardial infarction (MI) can include:
- pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone;
- discomfort radiating to the back, jaw, throat, arm, stomach;
- feeling of being full, having indigestion or choking;
- sweating, nausea, vomiting or dizziness;
- extreme weakness, anxiety, or shortness of breath;
- rapid or irregular heartbeats.

Tumours
•   An increased risk of cervical cancer in long-term users of COCs (> 5 years) has been reported in some epidemiological studies, but there continues to be controversy about the extent to which this finding is attributable to the confounding effects of sexual behaviour and other factors such as human papilloma virus (HPV). No epidemiological data on the risk of cervical cancer in users of Zoely are available.
•   With the use of the higher-dosed COCs (50 micrograms 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 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. 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.

Meningioma
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.

Hepatitis C
• During clinical trials with the hepatitis C virus (HCV) combination 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. Additionally, also in patients treated with glecaprevir/pibrentasvir, ALT elevations were observed in women using ethinylestradiol-containing medications 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 glecaprevir/pibrentasvir See section 4.5.

Other conditions
•    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.
•    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.
•    Exogenous oestrogens may induce or exacerbate symptoms of hereditary and acquired 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.
•     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.
• Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use (see section 4.8). Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their physician in case of mood changes and depressive symptoms, including shortly after initiating the treatment.

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 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.

Reduced efficacy

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

Cycle control

With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially 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.

Paediatric population
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).

Laboratory tests
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.

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

Effects on Driving

4.7   Effects on ability to drive and use machines

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