Medical Examination/Consultation
Prior to the initiation or reinstitution of Millinette 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 Millinette 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.
Warnings
If any of the conditions or risk factors mentioned below is present, the suitability of Millinette 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 Millinette 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 Millinette 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 Millinette, 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.
Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral 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).
Millinette 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 Millinette 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. |
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 “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 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). Millinette 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, 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 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.
Biochemical factors indicating hereditary or acquired predisposition for venous or arterial thrombosis, include activated protein C (APC) resistance, hyperhomocysteinaemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).
When weighing the advantages/disadvantages the physician should take into consideration that adequate treatment of a given condition may reduce the risk associated with thrombosis and that the risk of developing thrombosis during pregnancy is higher than with low-dose COCs (<50 microgram ethinylestradiol).
Tumours
Cervical cancer
The most important risk factor for cervical cancer is persistent HPV infection. Some epidemiological studies have indicated that long-term use of COCs may further contribute to this increased risk but there continues to be controversy about the extent to which this finding is attributable to confounding effects, e.g., cervical screening and sexual behaviour including use of barrier contraceptives.
Breast cancer
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 combined oral contraceptives (COCs). The excess risk gradually disappears during the course of the 10 years after stopping COC. As breast cancer is rare among women under 40 years the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer in their complete life time. 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. The additional breast cancers diagnosed in current users of COCs or in women who have used COCs in the last ten years are more likely to be localised to the breast than those in women who never used COCs.
With the use of the higher-dosed COCs (0.05 mg ethinylestradiol) the risk of endometrial and ovarian cancer is reduced. Whether this also applies to lower-dosed COCs remains to be confirmed.
Hepatic neoplasia/liver disease
In rare cases benign and, in even rarer cases, malignant liver tumours have been reported. In isolated cases these tumours have led to life-threatening intra-abdominal haemorrhage. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, the possibility of a liver tumour should be included in the differential diagnosis in women taking COCs.
Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal.
Other conditions
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.
Women with hypertriglyceridaemia, or a family history thereof, may be at increased risk of pancreatitis when taking COCs.
Even though slight increases in blood pressure have been reported in many women taking COCs, clinically important increases in blood pressure are rare. If persistent clinical hypertension develops during COC use, intake should be discontinued and the hypertension treated. Use of COCs may be resumed, if appropriate, when normotensive values are reached with antihypertensive therapy.
It has been reported that the following conditions may occur, or worsen both during pregnancy and during use of COCs, but the evidence of a relationship is inconclusive: Jaundice and/or pruritus in connection with cholestasis; development of gallstones; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham's chorea; herpes gestationis; loss of hearing due to otosclerosis.
Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. Re-emergence of cholestatic jaundice which first occur during pregnancy or previous use of sex hormones requires withdrawal of the use of COCs.
There are reports about liver damage when using CHCs. Early identification of drug related liver damage may reduce the severity of liver toxicity upon withdrawal of the drug. If liver damage is diagnosed the patient must stop using oral contraceptives, use non-hormonal contraception and contact her physician.
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 <50 microgram ethinylestradiol). However, diabetic women should be carefully monitored, particularly in the early stage of COC use.
Crohn's disease and colitis ulcerosa have been associated with the use of combined oral contraceptives.
Chloasma may occur, in particular in women with a medical history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to sunlight or ultraviolet radiation while taking COCs.
Migraine/headache
Women with migraine (especially migraine with aura) using CHCs may have an increased risk of having a stroke.
The immune system
Angioedema
Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.
Herbal preparations containing St John's wort (Hypericum perforatum) should not be used while taking Millinette due to the risk of decreased plasma concentrations and reduced clinical effects of Millinette (see section 4.5).
Reduced efficacy
The efficacy of oral contraceptives may be reduced in the case of missed tablets or vomiting (see section 4.2) or concomitant use of other medicinal product (see section 4.5).
Reduced cycle control
With all combined oral contraceptives, irregular bleeding (spotting or break through bleeding) may occur, especially during the first months. Hence, the evaluation of any irregular bleeding should be considered after a period of adaptation of approximately 3 cycles.
If bleeding irregularities 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. If non-hormonal causes are ruled out recommending COC with a higher hormone content may be considered.
In some women withdrawal bleeding may not occur during the tablet-free interval. If the tablets have been taken according to the instructions described in section 4.2, it is unlikely that the woman is pregnant. However, if the tablets have not been taken according to the instructions, before the first absent withdrawal bleeding or if two withdrawal bleeds are missed, pregnancy must be ruled out before COC use is continued.
Excipients
This medicinal product contains lactose and sucrose.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, glucose-galactose malabsorption, fructose intolerance or sucrase-isomaltase insufficiency should not take this medicine.
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.
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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