Special Warning : אזהרת שימוש

4.4      Special warnings and precautions for use

If any of the conditions or risk factors mentioned below is present, the suitability of Minesse 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 Minesse should be discontinued.

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. Other products such as Minesse may have up to twice this level of risk. The decision to use any product other than one with the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with Minesse, 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).

It is estimated1 that out of 10,000 women who use a CHC containing gestodene between 9 and 12 women will develop a VTE in one year; this compares with about 62 in women who use a levonorgestrel-containing CHC.

In both cases, the number of VTEs per year is fewer than the number expected during pregnancy or in the postpartum period.

VTE may be fatal in 1-2% of cases.



1 These incidences were estimated from the totality of the epidemiological study data, using relative risks for the different products compared with levonorgestrel-containing CHCs.
2 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
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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).

Minesse 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             In these situations it is advisable to discontinue use of surgery to the legs or pelvis, neurosurgery, or          the pill (in the case of elective surgery at least four major trauma                                             weeks in advance) and not resume until two weeks after complete remobilisation. Another method of contraception should be used to avoid unintentional pregnancy.

Note: temporary immobilisation including air             Antithrombotic treatment should be considered if travel >4 hours can also be a risk factor for            Minesse has not been discontinued in advance.
VTE, particularly in women with other risk factors
Positive family history (venous                          If a hereditary predisposition is suspected, the woman thromboembolism ever in a sibling or parent              should be referred to a specialist for advice before especially at a relatively early age e.g. before         deciding about any CHC use Page 5 of 18                                          2022-0081366
50).
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 
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). Minesse is contraindicated if a woman has one Page 6 of 18                                         2022-0081366
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            Risk increases substantially as BMI increases.
kg/m2)
Particularly important in women with additional risk factors
Positive family history (arterial           If a hereditary predisposition is suspected, the woman thromboembolism ever in a sibling or        should be referred to a specialist for advice before parent especially at relatively early age   deciding about any CHC use e.g. below 50).
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         Diabetes mellitus, hyperhomocysteinaemia, valvular with adverse vascular events                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 myocardial infarction (MI) can include:
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- 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.

Gynaecological cancers

A meta-analysis of data from 54 international studies demonstrated a slightly higher risk of breast cancer diagnosis among users of oral contraceptives. This increased risk does not appear to be dependent upon the duration of use. The influence of risk factors such as nulliparity or a family history of breast cancer is not established.

This increased risk is transient and disappears 10 years after the oral contraceptive is discontinued.

It is possible that the more regular clinical monitoring of women taking oral contraceptives, with increased likelihood of earlier diagnosis, may play an important role in the higher number of breast cancers diagnosed.

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 lifetime risk of breast cancer.
Breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.

An increased risk of cervical cancer in long-term users of COCs has been reported in some epidemiological studies. However, there continues to be controversy about the extent to which these findings may be due to the confounding effects of sexual behaviour and other factors such as human papilloma virus (HPV).

The published data do not compromise the use of oral contraceptives, as the potential risks appear to be outweighed by the benefits.

In addition, oral contraception decreases the risk of ovarian and endometrial cancers.

Hepatic neoplasia/liver disease
In rare cases benign liver tumours (e.g. focal nodular hyperplasia, hepatic adenomas) 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 haemorrhage.

Cholestasis has been reported to occur or deteriorate with both pregnancy and COC use, but the evidence of an association with COC use is inconclusive.

Hepatic and hepatobiliary disorders have been reported with COC use. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal.

Headache
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The onset or exacerbation of migraine or development of headache with a new pattern that is recurrent, persistent, or severe requires discontinuation of COCs and evaluation of the cause.

Hypertension

Although uncommon, increases in blood pressure have been reported in women taking COCs.
In women with hypertension, a history of hypertension or hypertension related diseases (including certain renal diseases), another method of contraception may be preferable. If COCs are used in such cases, close monitoring is recommended and, if a significant increase in blood pressure occurs, COCs should be discontinued.

Other

Medical examination/consultation
Prior to the initiation or reinstitution of Minesse 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 contra-indications (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 Minesse 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 HIV infections (AIDS) and other sexually transmitted diseases.

Caution should be exercised in women with:
- Metabolic disorders such as uncomplicated diabetes.
- Hyperlipidemia (hypertriglyceridemia, hypercholesterolemia). Women who are being treated for hyperlipidemias should be followed closely if they elect to use COCs.
Persistent hypertriglyceridemia may occur in a small proportion of COC users.

In patients with elevated triglycerides, estrogen-containing preparations may be associated with rare but large elevations of plasma triglycerides that may lead to pancreatitis.

Obesity (body mass index=Weight/Height230)

Benign tumours of the breast and uterine dystrophy (hyperplasia, fibroma) 
Hyperprolactinemia with or without galactorrhea.

Close surveillance should also be ensured in the presence of conditions, which have been reported to occur or deteriorate with pregnancy or COC use, respectively in patients presenting or with a history of: epilepsy, migraine, otosclerosis, asthma, family history of vascular disease, varicose veins, herpes gestationis, gallstones, systemic lupus erythematosus, cardiac, renal or hepatic dysfunction, depression, hypertension, chorea, haemolytic uremic syndrome.

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

In clinical trials, amenorrhea, not linked to pregnancy, was observed in 7% of cycles (occurring in 24% of women over the total duration of the clinical trials) and 3.6% of women experienced
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consecutive amenorrheic cycles. In the clinical trials, only and 1% of women discontinued because of amenorrhea.

When Minesse is taken according to directions, in the occurrence of one amenorrheic cycle, there is no reason for discontinuation and performance of a pregnancy test. If Minesse is not taken according to directions or if amenorrhea occurs after a long period of regular menstrual bleeding, pregnancy should be ruled out.

Some women may encounter post-therapeutic amenorrhea (possibly with anovulation) or oligomenorrhea, especially when such a condition was pre-existing. It usually resolves spontaneously. If prolonged, investigations should be carried out into the possibility of pituitary disorders before any further prescription.

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 three cycles.

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. Further diagnostic measures may include curettage.

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.

If melasma/chloasma has appeared during pregnancy or with previous COC use, exposure to sunlight should be avoided to minimize exacerbation of this condition.

Diarrhea and/or vomiting may reduce COC hormone absorption (see section 4.2).

Women should be advised that hormonal contraceptives do not protect against HIV infection (AIDS) or other sexually transmitted diseases.

Due to the presence of lactose, this medicinal product is not recommended for use in women with lactose intolerance.

Effects on Driving

4.7        Effects on ability to drive and use machines

The impact of Minesse on the ability to drive and use machines has not been systematically evaluated. Minesse is not expected to influence the ability to drive or use machines. Cases of dizziness have been reported. Patients should exercise caution until they know that Minesse does not affect these abilities.