| Warnings: Like many other steroids, Dianette, when given in very high doses and for the majority of the animal's life-span, has been found to cause an increase in the incidence of tumours, including carcinoma, in the liver of rats. The relevance of this finding to humans is unknown. In rare cases benign and in even rarer cases malignant liver tumours leading in isolated cases to life-threatening intra-abdominal haemorrhage have been observed after the use of hormonal substances such as those contained in Dianette. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, a liver tumour should be included in the differential diagnosis. Animal studies have revealed that feminisation of male foetuses may occur if cyproterone acetate is administered during the phase of embryogenesis at which differentiation of the external genitalia occurs. Although the results of these tests are not necessarily relevant to man, the possibility must be considered that administration of Dianette to women after the 45th day of pregnancy could cause feminisation of male foetuses. It follows from this that pregnancy is an absolute contra-indication for treatment with Dianette, and must be excluded before such treatment is begun. Dianette is composed of the progestogen cyproterone acetate and the oestrogen ethinylestradiol and is administered for 21 days of a monthly cycle. It therefore has a similar composition to that of a combined oral contraceptive (COC). The use of any COC or Dianette carries an increased risk for venous thromboembolism (VTE), including deep venous thrombosis and pulmonary embolism, 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 per 100,000 pregnancies. Full recovery from such disorders does not always occur; VTE is fatal in 1-2% of cases. Epidemiological studies have shown that the incidence of VTE in users of oral contraceptives with low oestrogen content (< 50 µg ethinylestradiol) is up to 40 cases per 100,000 women-years. This compares with 5-10 cases per 100,000 women-years for non-users. Certain factors may increase the risk of venous thrombosis e.g. severe obesity (body mass index > 30kg/m2), increasing age, a genetic predisposition to clotting or a personal or family history of confirmed, idiopathic VTE (where family history refers to VTE in a sibling or parent at a relatively early age, see contraindications section 4.3). In addition, the risk of VTE may be temporarily increased by prolonged immobilisation, major surgery, any surgery to the legs, or major trauma (see “Reasons for stopping Dianette immedicately”). There is some epidemiological evidence that the incidence of VTE is higher in users of Dianette when compared to users of COCs with low oestrogen content (< 50µg). The user group of Dianette as a treatment for severe acne or moderately severe hirsutism is likely to include patients that may have an inherently increased cardiovascular risk such as that associated with polycystic ovarian syndrome. Epidemiological studies have also associated the use of COCs with an increased risk for arterial (myocardial infarction, transient ischaemic attack) thromboembolism. Certain factors such as smoking, obesity, cardiovascular disease, hypertension, diabetes and migraine may increase the risk of arterial thromboembolism. The risk of arterial thrombosis associated with oral contraceptives increases with age, and this risk is aggravated by cigarette smoking. Numerous epidemiological studies have been reported on the risks of ovarian, endometrial, cervical and breast cancer in women using combined oral contraceptives. The evidence is clear that combined oral contraceptives offer substantial protection against both ovarian and endometrial cancer. An increased risk of cervical cancer in long-term users of combined oral contraceptives has been reported in some studies, but there continues to be controversy about the extent to which this is attributable to the confounding effects of sexual behaviour and other factors. 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 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. Breast cancer is rare among women under 40 years of age whether or not they take COCs. Whilst this background risk increases with age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer (see bar chart). The most important risk factor for breast cancer in COC users is the age women discontinue the COC; the older the age at stopping, the more breast cancers are diagnosed. Duration of use is less important and the excess risk gradually disappears during the course of the 10 years after stopping COC use such that by 10 years there appears to be no excess. The possible increase in risk of breast cancer should be discussed with the user and weighed against the benefits of COCs taking into account the evidence that they offer substantial protection against the risk of developing certain other cancers (e.g. ovarian and endometrial cancer).Estimated cumulative numbers of breast cancers per 10,000 women diagnosed in 5 years of use and up to 10 years after stopping COCs, compared with numbers of breast cancers diagnosed in 10,000 women who had never used COCs The possibility cannot be ruled out that certain chronic diseases may occasionally deteriorate during the use of Dianette (see Precautions) Reasons for stopping Dianette immediately: 1. Occurrence for the first time, or exacerbation, of migrainous headaches or unusually frequent or unusually severe headaches. 2. Sudden disturbances of vision or hearing or other perceptual disorders. 3. First signs of thrombophlebitis or thromboembolic symptoms (e.g. unusual pains in or swelling of the leg(s), stabbing pains on breathing or coughing for no apparent reason). Feeling of pain and tightness in the chest. 4. Six weeks before an elective major operation (e.g. abdominal, orthopaedic), any surgery to the legs, medical treatment for varicose veins or prolonged immobilisation, e.g. after accidents or surgery. Do not restart until 2 weeks after full ambulation. In case of emergency surgery, thrombotic prophylaxis is usually indicated e.g. subcutaneous heparin. 5. Onset of jaundice, hepatitis, itching of the whole body. 6. Increase in epileptic seizures. 7. Significant rise in blood pressure. 8. Onset of severe depression. 9. Severe upper abdominal pain or liver enlargement. 10. Clear worsening of conditions known to deteriorate during use of hormonal contraception or during pregnancy. 11. Pregnancy is a reason for stopping immediately because it has been suggested by some investigations that oral contraceptives taken in early pregnancy may slightly increase the risk of foetal malformations. Other investigations have failed to support these findings. The possibility therefore cannot be excluded, but it is certain that if a risk exists at all, it is small. Precautions: Assessment of women prior to starting oral contraceptives (and at regular intervals thereafter) should include a personal and family medical history of each woman. Physical examination should be guided by this and by the contraindications (section 4.3) and warnings (section 4.4) for this product. The frequency and nature of these assessments should be based upon relevant guidelines and should be adapted to the individual woman, but should include measurement of blood pressure and, if judged appropriate by the clinician, breast , abdominal and pelvic examination including cervical cytology.The following conditions require strict medical supervision during medication with oral contraceptives. Deterioration or first appearance of any of these conditions may indicate that Dianette should be discontinued: Diabetes mellitus, or a tendency towards diabetes mellitus (e.g. unexplained glycosuria), hypertension, varicose veins, a history of phlebitis, otosclerosis, multiple sclerosis, epilepsy, porphyria, tetany, disturbed liver function, Sydenham's chorea, renal dysfunction, family history of clotting disorders, obesity, family history of breast cancer and patient history of benign breast disease, clinical depression, systemic lupus erythematosus, uterine fibroids, an intolerance to contact lenses, migraine, gall-stones, cardiovascular diseases, chloasma, asthma, or any disease that is prone to worsen during pregnancy. Patients with a history of depression or any condition mentioned above should be monitored during treatment with Dianette. If Dianette is discontinued, other methods of contraception should be introduced if needed. It should be borne in mind that the use of ultraviolet lamps, for the treatment of acne, or prolonged exposure to sunlight, increases the risk of the deterioration of chloasma. Some women may experience amenorrhoea or oligomenorrhoea after discontinuation of Dianette, especially when these conditions existed prior to use. Women should be informed of this possibility. | |