Special Warning : אזהרת שימוש

4.4       Special warnings and precautions for use

Warnings
Smoking increases the risk of severe cardiovascular side-effects of combination oral contraceptives (COC). This risk increases with increasing age and cigarette consumption and is very pronounced in women above the age of 35 years. Smokers over the age of 35 years should use other contraceptive methods.

Combined hormonal contraceptives administration is associated with an increased risk of various serious diseases such as myocardial infarction, thrombo-embolism, stroke, or hepatic neoplasms. Other risk factors such as hypertension, hyperlipidaemia, obesity and diabetes distinctly increase the morbidity and mortality risk.
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If any of the conditions or risk factors mentioned below is present, the suitability of Belara should be discussed with the patient.
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If any of these conditions or risk factors are aggravated or emerge for the first time, the woman should be advised to seek the advice of her treating doctor, who will subsequently decide whether the use of Belara should be discontinued.

Thromboembolism and other vascular diseases
Epidemiological studies have shown an association between hormonal contraceptive use and an increased risk of venous or arterial thromboembolic diseases such as myocardial infarction, apoplexy, deep vein thrombosis and pulmonary embolism. These events are uncommon. Extremely rarely, thrombosis has been reported to occur in combined hormonal contraceptive users in other blood vessels, e.g. hepatic, mesenteric, renal or retinal veins and arteries.

Risk of Venous thromboembolism (VTE)
The use of any combined hormonal contraceptive entails a higher risk of venous thromboembolism (VTE) than if the product is not used. Products that contain levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. It is not yet known how the risk with Belara compares with the risk with levonorgestrel-containing products. 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 patient, thereby ensuring that she has understood the risk of VTE associated with Belara, and furthermore how her existing risk factors affect this risk, and that she is aware that the risk of VTE risk is at its highest in the first ever year of use. There is also some evidence that the risk is increased when the use of a combined hormonal contraceptive is resumed following a respite in its use for 4 weeks or more.

In women who do not use a combined hormonal contraceptive and are not pregnant, about 2 out of 10,000 will develop a VTE during a one-year period. 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 combined hormonal contraceptives (CHC) (<50pg ethinylestradiol) have found that out of 10,000 women about 6 to 12 will develop a VTE in one year.

Out of 10,000 women who use a levonorgestrel-containing CHC about 61 will develop a VTE in one year.

It is not yet know how the risk with chlormadinone-containing CHCs compares with the risk with levonorgestrel-containing CHCs.

This annual number of VTEs is lower than the number expected during pregnancy or in the postpartum period. The VTE may have a fatal outcome in 1-2% of cases.

Risk factors for VTE
The risk for venous thromboembolic complications in combined hormonal contraceptive users may increase substantially in a woman with additional risk factors, particularly if several of the risk factors are present (see table).
Belara is contraindicated if a woman has multiple risk factors that put her at high risk of developing 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 f actors – in this case her total risk of VTE should be taken into consideration. If the balance of benefits and risks is considered to be negative a combined hormonal contraceptive should not be prescribed (see section 4.3).



1Mid-point of range of 5-7 per 10,000 WY, based on a relative risk for combined hormonal contraceptives containing levonorgestrel, versus the  approximately 2.3-3.6 range observed without the use of such products.
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Table: Risk factors for VTE
Risk factor                               Notes
Obesity (body mass index greater than 30 Risk increases significantly with an increase in the BMI.
kg/m2)                                    It is particularly important to take this into consideration if other risk factors also present.
Prolonged immobilisation, major surgery, In these situations, it is advisable to discontinue use of the any surgery to the lower limbs or pelvis, patch/pill/ring (at least 4 weeks prior to elective surgery) neurosurgery, or major trauma             and to only resume its use after two weeks have elapsed following full remobilisation. Another method of contraception should be used to avoid unintentional pregnancy.
Antithrombotic therapy should be considered if the use of
Note: temporary immobilisation,           Belara has not been discontinued in advance.
including air travel of >4 hours can also be a risk factor for VTE, particularly in women with other risk factors.
Positive family history (venous            If a hereditary predisposition is suspected, advice should thromboembolism at any time in a sibling be sought from a specialist before any decision is made or parent, especially if it developed at a with regard to the use of a combined hormonal relatively early age, e.g. before 50).     contraceptive.
Other medical conditions associated with Cancer, systemic lupus erythematosus, haemolytic VTE                                      uraemic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell anaemia
Advanced 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 puerperium period, must be considered (for information on “Fertility, 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 they are taking a combined hormonal contraceptive.

Symptoms of deep vein thrombosis (DVT) can include:
-    swelling of the lower leg and/or foot on one side or along a vein in the leg; -    pain or tenderness in the leg, which may be felt by the patient 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 may be confused with more common or less severe events (e.g. respiratory tract infections).
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Other signs of vascular occlusion can include sudden pain, swelling and the slight blueish discoloration of an extremity.

If the occlusion occurs in the eye, symptoms can range from a painless blurring of vision to progressive loss of vision. Sometimes the loss of vision occurs almost immediately.

Risk of arterial thromboembolism (ATE)
Epidemiological studies have associated the use of combined hormonal contraceptives with an increased risk for arterial thromboembolism (myocardial infarction) or for cerebrovascular accident (e.g. transient ischaemic attack, stroke). Arterial thromboembolic events can be fatal.

Risk factors for ATE
The risk of arterial thromboembolic complications (myocardial infarction) or of a cerebrovascular accident in combined hormonal contraceptive users increases in women with risk factors (see table).
Belara is contraindicated if a woman has one serious risk factor, or multiple risk factors, that put her at a 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 taken into consideration. If the balance of benefits and risks is considered to be negative a combined hormonal contraceptive should not be prescribed (see section 4.3).

Table: Risk factors for ATE
Risk factor                                 Notes
Advanced age                                Particularly above 35 years Smoking                                     Women should be advised not to smoke if they wish to use a combined hormonal contraceptive. 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           Risk increases substantially as BMI increases. This is kg/m2)                                     especially important in women with additional risk factors.
Positive family history (arterial          If a hereditary predisposition is suspected, advice should thromboembolism at any time in a sibling be sought from a specialist before any decision is made or parent, especially if it developed at a with regard to the use of a combined hormonal relatively early age, e.g. before 50).     contraceptive.
Migraine                                 The frequency or severity of migraine may increase during combined hormonal contraceptive use (which may be the precursor of a cerebrovascular event), and therefore it my be a reason for immediately discontinuing the use of the product.
Diabetes mellitus, hyperhomocysteinaemia, valvular heart
Other medical conditions associated with disease and atrial fibrillation, dyslipoproteinaemia and adverse vascular events                  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 they are taking a combined hormonal contraceptive.

Symptoms of a cerebrovascular accident can include:
- sudden numbness or weakness of the face, arm or leg, especially on one side of the body 9
-   sudden difficulty walking, dizziness, loss of balance or coordination; -   sudden confusion, trouble speaking or understanding speech;
-   sudden difficulty seeing in one or both eyes;
-   sudden, severe or prolonged headache with no known cause
-   loss of consciousness or fainting, with or without a seizure.
Temporary symptoms suggest that the event is a transient ischaemic attack (TIA).

Symptoms of 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 fullness or indigestion, or a feeling of suffocation; -    sweating, nausea, vomiting or dizziness;
-    extreme weakness, anxiety, or shortness of breath;
-    rapid or irregular heartbeat;

Women who are taking combined hormonal contraceptives should be informed that they should consult their doctor if they develop possible symptoms of thrombosis. Belara should be stopped if thrombosis is suspected or confirmed.

Tumours
Some epidemiological studies indicate that the long-term use of hormonal contraceptives is a risk factor for the development of cervical cancer in women infected with the human papilloma virus (HPV).
However, there is still controversy about the extent to which this finding is influenced by confounding effects (e.g. differences in the number of sexual partners or the use of mechanical contraceptive measures) (see also "Medical examination").

A meta-analysis from 54 epidemiological studies reported a slightly increased risk (RR = 1.24) of breast cancer in women who are currently using CHCs. This increased risk is transient and during the course of 10 years after cessation of CHC use this risk gradually decreases. These studies do not suggest evidence for causation. It is possible that this increased risk observed may be due to factors such as: early diagnosis of breast cancer in women taking combined hormonal contraceptives, the biological effects of combined hormonal contraceptives, or a combination of the two factors.

In rare cases benign, and in even fewer cases malignant, liver tumours have been reported during the administration of oral contraceptives. In isolated cases these tumours have led to life-threatening intra- abdominal haemorrhage. In the event of severe abdominal pain that does not recede spontaneously, hepatomegaly or signs of intra-abdominal haemorrhage the possibility of a liver tumour must be taken into account and Belara must be discontinued.

Meningioma:

The occurrence of meningiomas (single and multiple) has been reported in association with use of chlormadinone acetate, especially at high doses and for prolonged time (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 chlormadinone acetate-containing treatment, must be stopped, as a precautionary measure.

There is some evidence that the meningioma risk may decrease after treatment discontinuation of chlormadinone acetate.


Other conditions

Depressed mood and depression are well-known adverse effects of hormonal contraceptive use (see section 4.8). Depression can be severe and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their doctor if they experience mood changes or 10 depressive symptoms, even immediately after starting treatment.

Many women taking hormonal contraceptives had a slight increase in blood pressure; however a clinically significant increase is rare. The connection between the administration of hormonal contraceptives and clinically manifest hypertension has not been confirmed. If there is a clinically significant increase in blood pressure during the administration of Belara, the preparation should be discontinued and the hypertension treated. Belara can be continued as soon as blood pressure values have returned to normal on antihypertensive therapy.

Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.

In women with a history of herpes gestationis there may be a herpes recurrence during CHC administration.
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In women with a history of hypertriglyceridaemia or a family history of such the risk of pancreatitis is increased during CHC administration. Acute or chronic disturbances of liver function may necessitate discontinuation of CHC use until the liver function values return to normal. Recurrence of cholestatic jaundice which occurred first during pregnancy or previous use of sex hormones necessitates discontinuation of CHCs.

CHCs may affect peripheral insulin resistance or glucose tolerance. Therefore diabetics should be monitored carefully whilst taking oral contraceptives.

Uncommonly, chloasma may occur, particularly in women with a history of chloasma gravidarum.
Women with a tendency to develop chloasma should avoid exposure to the sun and ultraviolet radiation during the administration of hormonal contraceptives.

Precautions
The administration of oestrogen or oestrogen/progestogen combinations may have negative effects on certain diseases/conditions. Special medical supervision is also necessary
•      epilepsy
•      multiple sclerosis
•      tetany
•      migraine (see section 4.3)
•      asthma
•      cardiac or renal insufficiency
•      chorea minor
•      diabetes mellitus (see section 4.3)
•      liver diseases (see section 4.3)
•      dyslipoproteinaemia (see section 4.3)
•      auto-immune diseases (including systemic lupus erythematosus)
•      obesity
•      hypertension (see section 4.3)
•      endometriosis
•      varicosity
•      phlebitis (see section 4.3)
•      coagulation disorders (see section 4.3)
•      mastopathy
•      myoma uteri
•      herpes gestationis
•      depression
•      chronic inflammatory bowel diseases (Crohn’s disease, ulcerative colitis; see section 4.8) 
Medical examination/consultation
Prior to starting or resuming the use of Belara, 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 risks of Belara as compared with those of other combined hormonal contraceptives, 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 patient information leaflet and follow the advice given. The frequency and nature of examinations should be based on established practice guidelines, and should be performed in a manner that is adapted to the individual woman.
Women should be advised that hormonal contraceptives do not protect against HIV infection (AIDS) and other sexually transmitted diseases.
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Impaired efficacy
Omission of a film-coated tablet (see "Irregular tablet administration"), vomiting or intestinal disorders including diarrhoea, the long-term concomitant administration of certain medicinal products (see section 4.5) or in very rare cases metabolic disorders may impair contraceptive efficacy.

The effect of the medicinal product on cycle control

Breakthrough bleeding and spotting
All oral contraceptives may cause irregular vaginal bleeding (breakthrough bleeding/spotting) particularly in the first few administration cycles. Therefore a medical assessment of irregular cycles should only be made after an adjustment period of about three cycles. If during administration of Belara breakthrough bleeding persists or occurs after previously regular cycles, an examination should be carried out to rule out pregnancy or an organic disorder. After pregnancy and an organic disorder have been ruled out, Belara can be continued or a switch made to another preparation.

Intracyclic bleeding may be a sign of impaired contraceptive efficacy (see "Irregular tablet administration", "Instructions in case of vomiting” and section 4.5).

Absence of withdrawal bleeding
After 21 days of administration withdrawal bleeding usually occurs. Occasionally and particularly in the first few months of administration withdrawal bleeding may be absent. However, this need not to be an indication of a reduced contraceptive effect. If bleeding is not present after one administration cycle in which a film-coated tablet was not forgotten, the tablet-free period of seven days was not extended, no other medicines were taken concomitantly, and there was no vomiting or diarrhoea, conception is unlikely and the administration of Belara can be continued. If Belara was not taken according to instructions before the first absence of withdrawal bleeding or withdrawal bleeding does not occur in two consecutive cycles, pregnancy must be ruled out before continuing administration.

Herbal medicines containing St-John's-wort (Hypericum perforatum) should not be taken together with Belara (see section 4.5).

Excipient
This medicine contains 69.5 mg of lactose monohydrate per tablet. This product should not be used in patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose- galactose malabsorption.

Effects on Driving

4.7       Effects on ability to drive and use machines

Combined hormonal contraceptives are not known to have negative effects on the ability to drive or to operate machines.
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