Relative ContraindicationsIf any of the conditions listed below is present, the benefits of COC use must be weighed against the possible risks for each individual woman and discussed with her before she decides to start using it. The patient should be kept under close supervision. In case of aggravation, exacerbation or appearance of any of these conditions or risk factors whilst the patient is taking the Pill, it's use should be discontinued, alternative non-hormonal methods of contraception used (not rhythm or temperature methods) and medical advice sought without delay.• Disorders of coagulation.• Other conditions associated with an increased risk of circulatory disease such as latent or overt cardiac failure, renal dysfunction, or a history of these conditions.• Epilepsy or a history of this condition.• Migraine or a history of this condition.• A history of cholelithiasis.• Presence of any risk factor for estrogen-dependent tumours; estrogen-sensitive gynaecological disorders such as uterine fibromyomata and endometriosis (See below; The Pill and cancer).• Diabetes mellitus.• Severe depression or a history of this condition. If this is accompanied by a disturbance in tryptophan metabolism, administration of vitamin B6 might be of therapeutic value.• Sickle cell haemoglobinopathy, since under certain circumstances, e.g. during infections or anoxia, estrogen-containing preparations may induce thromboembolic process in patients with this condition.• If the results of liver function tests become abnormal, use should be discontinued.
The Pill and Thrombosis• Some epidemiological studies have suggested an association between the use of COCs and an increased risk of arterial and venous thrombotic and thromboembolic diseases such as myocardial infarction, stroke, deep venous thrombosis, and pulmonary embolism. These events occur rarely. • An increased risk of venous thromboembolic disease (VTE) associated with the use of oral contraceptives is well established. The excess risk of VTE is highest during the first year a woman ever uses a combined oral contraceptive. It is smaller than the risk associated with pregnancy, which has been estimated at 60 cases per 100,000 pregnancies. Some epidemiological studies have reported a greater risk of VTE for women using combined oral contraceptives containing desogestrel or gestodene (the so-called third generation pills) than for women using pills containing levonorgestrel (the so-called second generation pills).• The spontaneous incidence of VTE in healthy non-pregnant women (not taking any oral contraceptive) is about 5 cases per 100,000 women per year. The incidence in users of second generation pills is about 15 per 100,000 women per year. The incidence in users of third generation pills is about 25 cases per 100,000 women per year of use: this excess incidence has not been satisfactorily explained by bias or confounding. The level of all these risks of VTE increases with age and is likely to be further increased in women with other known risk factors for VTE such as obesity.• Thrombosis has very rarely been reported to occur in other veins or arteries, e.g. hepatic, mesenteric, renal or retinal, in COC users. There is no consensus as to whether the occurrence of these events is associated with the use of COCs.• The risk of thromboembolism (venous and/or arterial) increases with:- age- smoking (with heavier smoking and increasing age the risk further increases, especially in women over 35 years of age)- a positive family history (i.e. venous or arterial thromboembolism 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 COC use- obesity (body mass index over 30kg/m2) - dyslipoproteinaemia, - hypertension - valvular heart disease- atrial fibrillation- diabetes- prolonged immobilisation, major surgery, any surgery to the legs, or major trauma. In these situations it is advisable to discontinue COC use (in the case of elective surgery at least four weeks in advance) and not to resume until two weeks after complete remobilisation.• There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism.• The increased risk of thromboembolism in the puerperium must be considered.• Other medical conditions which have been associated with adverse circulatory events include diabetes mellitus, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell disease.• An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC.• Biochemical factors that may be indicative of hereditary or acquired predisposition for venous or arterial thrombosis include Activated Protein C (APC) resistance, hyper homocysteinaemia, antithrombin-III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant). • 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. • Signs and symptoms of a thrombotic event may include:
| ||• sudden severe pain in the chest, whether or not reaching to the left arm; • sudden breathlessness; • any unusual severe, prolonged headache, especially if it occurs for the first time or gets progressively worse, or is associated with any of the following symptoms:|
| ||- sudden partial or complete loss of vision or diplopia- aphasia- vertigo- a bad fainting attack - collapse with or without focal epilepsy- weakness or very marked numbness suddenly affecting one side or one part of the body- motor disturbances- severe pain in the calf of one leg- 'acute' abdomen.|
The Pill and Cancer• The use of estrogen-containing oral contraceptives may promote growth of existing sex steroid dependent tumours. For this reason, the use of these oral contraceptives in patients with such tumours is contraindicated.• 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 • Malignant hepatic tumours have been reported on rare occasions in long-term users of oral contraceptives. Benign hepatic tumours have also been associated with oral contraceptive usage. A hepatic tumour should be considered in the differential diagnosis when upper abdominal pain, enlarged liver or signs of intra-abdominal haemorrhage occur.
Reduced reliabilityWhen Marvelon is taken according to the directions for use the occurrence of pregnancy is highly unlikely. However, the reliability of oral contraceptives may be reduced under the following circumstances:
Forgotten TabletsProvided she is less than 12 hours late in taking her tablet the patient should take it as soon as she remembers. Further tablets should be taken at the usual time. Marvelon will still give contraceptive protection during this cycle.If she is more than 12 hours late in taking one or more tablets then she will not be protected for the next 7 days.If one or more tablets are forgotten for more than 12 hours, contraceptive protection will be reduced. The patient should take the last forgotten tablet, even if this means taking two tablets in one day, and then continue to take tablets at the normal time. Additional contraceptive precautions should be taken for the next 7 days, and the patient should follow the '7-day rule'.
Vomiting or Diarrhoea If after tablet intake vomiting or diarrhoea occurs, a tablet may not be absorbed properly by the body. If the symptoms disappear within 12 hours of tablet-taking, the patient should take an extra tablet from a spare pack and continue with the rest of the pack as usual. However, if the symptoms continue beyond those 12 hours, additional contraceptive precautions are necessary for any sexual intercourse during the stomach or bowel upset and for the following 7 days (the patient must be advised to follow '7-day rule').
If the patient is taking certain other medicinesIf the patient is taking any of the medicines given in the 'Interactions' section she should be advised to follow the '7-day rule':
If after taking Marvelon for several months there is a sudden occurrence of spotting or breakthrough bleeding (not observed in previous cycles) or the absence of withdrawal bleeding, contraceptive effectiveness may be reduced. If withdrawal bleeding fails to occur and none of the above mentioned events has taken place, pregnancy is highly unlikely and oral contraceptive use can be continued until the end of the next pack.( If withdrawal bleeding fails to occur at the end of the second cycle, tablet intake should be discontinued and pregnancy excluded before oral contraceptive use can be resumed.) However, if withdrawal bleeding is absent and any of the above mentioned events has occurred, tablet intake should be discontinued and pregnancy excluded before oral contraceptive use can be resumed.
THE 7-DAY RULE
If any one
tablet is forgotten for more than 12 hours
If the patient has vomiting or diarrhoea for more than 12 hours:
If the patient is taking any of the drugs listed under 'Interactions':
The patient should continue to take her tablets as usual and:
• Additional contraceptive precautions must be taken for the next 7 days
• BUT - if these 7 days run beyond the end of the current pack, the next pack must be started as soon as the current one is finished, i.e. no gap should be left between packs. (This prevents an extended break in tablet taking which may increase the risk of the ovaries releasing an egg and thus reducing contraceptive protection). The patient will not have a period until the end of 2 packs but this is not harmful nor does it matter if she experiences some bleeding on tablet taking days.
Medical Examination/consultationAssessment 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.Caution should be observed when prescribing oral contraceptives to young women whose cycles are not yet established.
ChloasmaChloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking this preparation.
Laboratory TestsThe use of steroids may influence the results of certain laboratory tests. In the literature, at least a hundred different parameters have been reported to possibly be influenced by oral contraceptive use, predominantly by the estrogenic component. Among these are: biochemical parameters of the liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins and lipid/lipoprotein fractions and parameters of coagulation and fibrinolysis.