Special Warning : אזהרת שימוש

4.4      Special warnings and precautions for use

Warnings
For any particular estrogen/progestin combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestin that is compatible with a low failure rate and the needs of the individual patient.

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

Risk of Venous Thromboembolism

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 Minulet may have up to twice this level of risk. 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 Minulet, 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


Number of VTE events per 10,000 women in one year


Epidemiological studies have shown that the incidence of VTE in women with no known risk factors for VTE who use low dose oestrogen (<50 mcg ethinylestradiol) combined hormonal contraceptives ranges from about 20 cases per 100,000 woman-years (for levonorgestrel- containing CHCs) to 40 cases per 100,000 women-years (for desogestrel/gestodene- containing CHCs).

For CHCs containing 30g of ethinylestradiol combined with desogestrel or gestodene (such as Minulet) compared with those containing less than 50g of ethinylestradiol and levonorgestrel, the overall risk of venous thrombotic and thromboembolic events has been estimated to range between 1.5 and 2.0. The incidence of venous thrombotic or thromboembolic events for levonorgestrel containing CHCs with less than 50g of ethinylestradiol is approximately 20 cases per 100,000 woman-years of use. For CHCs containing 30g of ethinylestradiol combined with desogestrel or gestodene the incidence is approximately 30-40 cases per 100,000 woman-years of use, i.e. additional 10-20 cases per 100,000 woman-years of use.

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 1).

Minulet 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 1: Risk factors for VTE
Risk factor                                 Comment
Obesity (body mass index over 30            Risk increases substantially as BMI rises.
kg/m²)                                      Particularly important to consider if other risk factors also present.
Prolonged immobilisation (including         In these situations it is advisable to discontinue use of air travel >4 hours), major surgery, any    the patch/pill/ring (in the case of elective surgery at surgery to the legs or pelvis,              least four weeks in advance) and not resume until two neurosurgery, or major trauma               weeks after complete remobilisation. Another method of contraception should be used to avoid unintentional pregnancy.
Antithrombotic treatment should be considered if
Minulet has not been discontinued in advance.

Note: temporary immobilisation including air travel >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, the woman thromboembolism ever in a sibling or        should be referred to a specialist for advice before parent especially at a relatively early     deciding about any CHC use age e.g. before 50).
Other medical conditions associated         Cancer, systemic lupus erythematosus, haemolytic with VTE.                                   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 (see section 4.6 and also graph on VTE risk).

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 2). Minulet 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 2: 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 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.

Carcinoma of the Reproductive Organs
 a. Cervical cancer
The most important risk factor for cervical cancer is persistent human papillomavirus infection.
Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia or invasive cervical cancer in some populations of women.
However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behaviour and other factors (see section 4.4).
 b. Breast cancer
A meta-analysis from 54 epidemiological studies showed that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using CHCs. The increased risk gradually disappears during the course of the 10 years after cessation of CHC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent CHC users is small in relation to the lifetime risk of breast cancer. These studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in CHC users, the biological effects of CHCs or a combination of both. Breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.

Hepatic Neoplasia/Liver Disease
In very rare cases, benign hepatic adenomas, and in extremely rare cases, hepatocellular carcinoma may be associated with CHC use. The risk appears to increase with duration of oral contraceptives use. Rupture of hepatic adenomas may cause death through intra-abdominal haemorrhage.

Studies have shown an increased risk of developing hepatocellular carcinoma in long-term oral contraceptive users; however, these cancers are extremely rare.


Women with a history of CHC-related cholestasis and women who develop cholestasis during pregnancy are more likely to develop cholestasis with CHC use. Such patients who use CHC should be carefully monitored, and CHC use should be discontinued if cholestasis recurs.

Hepatocellular injury has been reported with CHC use. Early identification of drug-related hepatocellular injury can decrease the severity of hepatotoxicity when the drug is discontinued. If hepatocellular injury is diagnosed, patients should stop their CHC, use a non- hormonal form of birth control and consult their doctor.

Acute or chronic disturbances of liver function may necessitate the discontinuation of the CHC use until liver function has returned to normal.

Ocular Lesions
There have been case reports of retinal thrombosis with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions.

Gallbladder Disease
An increased relative risk of gallbladder disease in users of oral contraceptives and estrogens has been reported in some studies.

Carbohydrate and Lipid Metabolic Effects
Glucose intolerance has been reported in oral contraceptive users. Some progestins are known to increase insulin secretion and create insulin resistance, while estrogens (> 75 g) may create a state of hyperinsulinism. Women with impaired glucose tolerance or diabetes mellitus should be carefully observed while taking oral contraceptives.

Due to alterations of glucose tolerance, the required dose of insulin or other antidiabetic agents might change.

A small proportion of women will have persistent hypertriglyceridemia while on the pill. A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents.

Hypertension
An increase in blood pressure has been reported in women taking oral contraceptives and this increase is more likely in older oral contraceptive users and with continued use. Data from the Royal College of General Practitioners and subsequent randomized trials have shown that the incidence of hypertension increases with increasing quantities of progestins.

Women with a history of hypertension or hypertension-related diseases, or renal diseases should be encouraged to use another method of contraception. If women with hypertension elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued.

CHC use is contraindicated in women with uncontrolled hypertension (see section 4.3).

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

Bleeding Irregularities
Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. The type and dose of progestin may be important. Non-hormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as 
in the case of any abnormal vaginal bleeding. If pathology has been excluded, continued use of the oral contraceptive or a change to another formulation may solve the problem.
In some women, withdrawal bleeding may not occur during the usual tablet free interval. If the CHC has been taken according to directions, it is unlikely that the woman is pregnant.
However, if the CHC has not been taken according to directions prior to the first missed withdrawal bleed or if two consecutive withdrawal bleeds are missed, tablet-taking should be discontinued and a non-hormonal back-up method of contraception should be used until the possibility of pregnancy is ruled out.
Some women may encounter post-pill amenorrhea (possibly with anovulation) or oligomenorrhea, especially when such a condition was preexistent.

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

Precautions

Medical examination/ consultation
Prior to the initiation or reinstitution of Minulet, 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 Minulet 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 and if judged appropriate by the clinician, should include breast, abdominal and pelvic examination including cervical cytology.

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

Lipid Disorders
Glucose intolerance has been reported in CHC users. Woman with impaired glucose tolerance or diabetes mellitus who use CHCs should be carefully monitored (see section 4.5).

A small proportion of women will have adverse lipid changes while taking oral contraceptives.
Persistent hypertriglyceridemia may occur in a small proportion of CHC users. Elevations of plasma triglycerides may lead to pancreatitis and other complications. Women who are being treated for hyperlipidaemias should be followed closely if they elect to use oral contraceptives. Some progestins may elevate low-density lipoprotein (LDL) levels and may render the control of hyperlipidaemias more difficult. Non-hormonal contraception should be considered in women with uncontrolled dyslipidaemias (see Warnings above).

Liver function
Acute or chronic liver dysfunction may necessitate the discontinuation of CHC use until liver function returns to normal. Steroid hormones may be poorly metabolized in patients with impaired liver function.

Emotional disorders
Patients becoming significantly depressed while taking oral contraceptives should stop the medication and use an alternate method of contraception in an attempt to determine whether the symptom is drug related. Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.

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.

Folate levels
Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.

St. John’s wort
If combined hormonal contraceptives (CHCs) and St. John’s wort are used concomitantly, a non-hormonal back-up method of birth control is recommended (see section 4.5).

Other
Diarrhoea and/or vomiting may reduce hormone absorption resulting in decreased serum concentration (see section 4.5).

The following conditions have been reported to occur or deteriorate with both pregnancy and CHC use, but the evidence of an association with CHC use is inconclusive: jaundice and/or pruritus related to cholestasis, porphyria, systemic lupus erythematosus, haemolytic uraemic syndrome, Sydenham´s chorea, herpes gestationis, otosclerosis-related hearing loss.


Excipient Information

Patients with rare hereditary problems of fructose or galactose intolerance, total lactase deficiency, sucrase-isomaltase insufficiency or glucose-galactose malabsorption should not take Minulet.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Effects on Driving

4.7     Effects on ability to drive and use machines

None known.