|Assessment and examination prior to starting combined oral contraceptivesBefore the start or resumption of treatment with combined oral contraceptives a complete personal and family medical history must be obtained and pregnancy should be ruled out. Blood pressure should be measured and a physical examination performed if clinically indicated, guided by the contraindications (see section 4.3) and warnings (see Warnings in this section). The woman should be instructed to carefully read the user leaflet and adhere to the advice given. The frequency and nature of further periodic checks should be based on established practice guidelines and adapted to the individual woman|
GeneralWomen should be advised that COCs do not protect against HIV (AIDS) or other sexually transmitted infections (STI). Cigarette smoking increases the risk of serious cardiovascular side effects from COC use. This risk increases with age and with the extent of smoking and is particularly marked in women over 35 years of age. All women who use COCs should be strongly advised not to smoke. Other methods of contraception should be considered for those women over 35 years old who smoke.If any of the risk factors below is present in any individual woman, the benefits of combined oral contraception must be weighed against possible risks in each individual case and discussed with the woman before combined oral contraception is commenced. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors the woman should be advised to contact her physician. The physician must then decide, whether the use of COCs should be discontinued.
Circulatory disorders The use of any COC carries an increased risk of venous thromboembolism (VTE) compared with no use. The excess risk of VTE is highest during the first year a woman ever uses a COC. This increased risk is less than the risk of VTE associated with pregnancy which is estimated as 60 cases per 100,000 pregnancies. VTE is fatal in 1-2% of cases. In several epidemiological studies it has been found that women using combined oral contraceptives with ethinylestradiol, mostly with a dose of 30 μg, and a progestin such as gestagen have an increased risk of VTE compared with those who using combined oral contraceptives containing less than 50 μg ethinylestradiol and the progestin levonorgestrel.For combined oral contraceptives containing 30 μg of ethinylestradiol combined with desogestrel or gestodene compared with those containing less than 50 μg of ethinylestradiol and levonorgestrel, the overall relative risk of VTE has been estimated to range between 1.5 and 2.0. The incidence of VTE for levonorgestrel containing combined oral contraceptives with less than 50 μg of ethinylestradiol is approximately 20 cases per 100,000 women-years of use. For Millinette the incidence is approximately 30-40 cases per 100,000 women-years of use, i.e. additional 10-20 cases per 100,000 women-years of use. The impact of the relative risk on the number of additional cases would be the greatest in women during the first year they ever use a combined oral contraceptive when the risk for VTE with all combined oral contraceptives is highest.Thrombosis in other blood vessels has very rarely been reported, i.e. hepatic, mesenteric, renal or retinal veins and arteries, in users of oral contraceptives. There is no consensus, whether the occurrence of these cases is related to use of COCs. The risk for development of venous thromboembolism increases with:− Increasing age.− A positive family history (e.g. venous thromboembolism in siblings or parents at a relatively young age). In the case of suspected hereditary predisposition, the woman should be referred to a specialist before she decides to use oral contraception.− Obesity (body mass index above 30 kg/m²).− Prolonged immobilisation, major surgery, surgery on the legs or major trauma. In such cases, it is recommended that treatment with oral contraceptives be discontinued (in the case of elective surgery at least 4 weeks prior to the operation) and should not be resumed until 2 weeks after complete remobilisation.− There is no consensus concerning the possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism.The use of COCs in general has been associated with an increased risk of acute myocardial infarction (AMI) or stroke, a risk that is strongly influenced by the presence of other risk factors (e.g. smoking, high blood pressure, and age) (see also below). These events occur rarely.The risk of arterial thromboembolic events increases with:− increasing age;− smoking (with heavier smoking and increasing age the risk further increases, especially in women over 35 years of age);− dyslipoproteinaemia;− obesity (body mass index over 30 kg/m2);− hypertension;− valvular heart disease;− atrial fibrillation;− a positive family history (i.e. arterial thrombosis ever in a sibling or parent at a relatively early age). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any hormonal contraceptive use.Symptoms of venous or arterial thrombosis can include: − unilateral leg pain and/ or swelling; − sudden severe pain in the chest, whether or not it radiates to the left arm; − sudden breathlessness; − sudden onset of coughing; − any unusual, severe, prolonged headache; − sudden partial or complete loss of vision; − diplopia; − slurred speech or aphasia; − vertigo; − collapse with or without focal seizure; − weakness or very marked numbness suddenly affecting one side or one part of the body; − motor disturbances; − 'acute' abdomen.The increased risk of venous thromboembolism during the puerperal period should be taken into consideration.Other medical conditions which have been related to circulatory disorders include diabetes mellitus, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn's disease or colitis ulcerosa) and sickle cell anaemia.An increase in the frequency or severity of migraine (which may be prodromal for a cerebrovascular condition) during use of oral contraceptives must lead to consideration of immediate discontinuation of oral contraceptives.Biochemical factors indicating hereditary or acquired predisposition for venous or arterial thrombosis, include activated protein C (APC) resistance, factor V Leiden mutation, hyperhomocysteinaemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant) and dyslipoproteinaemia.When considering risk/benefit, the physician should take into account that adequate treatment of a condition may reduce the associated risk of thrombosis and that the risk associated with pregnancy is higher than that associated with COC use.
Cervical cancerIn some epidemiological studies an increased risk of cervical cancer has been reported in long term users of COCs, but it is still not clear to which extent this finding may be influenced by impacts of sexual behaviour and other factors, such as human papilloma virus (HPV).
Breast cancerA meta-analysis from 54 epidemiological studies has shown that women using combined oral contraceptives have a slightly increased relative risk (RR=1.24) of having breast cancer diagnosed. This increased risk gradually declined over 10 years following cessation of COC use. Since breast cancer is a rare condition in women below 40 years of age, the increase in number of diagnosed cases of breast cancer in current and previous users of COCs is small compared to the risk of breast cancer during their entire life time.These studies do not present evidence for a causal relationship. The observed pattern of an increased risk may be caused by an earlier diagnosing of breast cancer in COC users, the biological effects of COCs or a combination of both.
Liver tumoursBenign and malignant liver tumours have been reported in users of COCs. These tumours have, in isolated cases, lead to life threatening, intra-abdominal haemorrhage. A liver tumour must be taken into consideration as a differential diagnosis when severe pain occurs in the upper abdomen, if there is hepatomegaly, or if there are signs of intra-abdominal haemorrhage in women taking COCs.
Other conditionsWomen with hypertriglyceridaemia, or a family history thereof, may be at increased risk of pancreatitis when taking COCs.In the case of acute or chronic impairment of liver function the use of Millinette should be stopped until liver function tests have returned to normal. Steroid hormones may be poorly metabolised in patients with impaired liver function.Hyperlipidaemic women should be closely monitored if they choose to use 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.COCs may have an influence on the peripheral insulin resistance and glucose tolerance. Therefore, diabetics should be closely monitored during COC use.Millinette contains lactose and sucrose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption or with rare hereditary problems of fructose intolerance should not take this medicinal product.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.There have been case reports of retinal thrombosis with the use of COCs. COCs should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilloedema; or retinal vascular lesions.Women who get severely depressed during the use of COCs should discontinue use and be advised to use an alternative contraceptive method while trying to determine if the symptoms are due to the COC preparation. Women who have previously suffered from episodes of major depression should be closely monitored and stop the use of the COC if the symptoms of depression relapse.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 efficacyThe 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 controlWith 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 persist COCs with a higher hormonal content may need to be considered. 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. Occasionally withdrawal bleeding during the tablet-free interval may not occur at all. 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 bleedings are overdue, pregnancy should be excluded before COC use is continued