If any of the conditions/risk factors mentioned below is present, the benefits of COC use should be weighed against the possible risks for each individual and discussed with the woman before she decides to start using it. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the woman should contact her physician. The physician should then decide on whether COC use should be discontinued.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 patientThe use of COCs is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and hypertension. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity, and particularly diabetes with vascular involvement.
1. Thromboembolic Disorders and Other Vascular Problems
Oral contraception must be used with caution in women with risk factors for thrombotic and thrombolic events or cardiovascular disease. Any of the following risk factors for venous or arterial disease may constitute an unacceptable level of risk.a. Myocardial InfarctionAn increased risk of myocardial infarction has been attributed to oral-contraceptive use. Smoking in combination with oral-contraceptive use has been shown to contribute substantially to the incidence of myocardial infarction in women in their mid-thirties or older with smoking accounting for the majority of excess cases. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and non smokers over the age of 40 among women who use oral contraceptives. All women who use oral contraceptives should be strongly advised not to smoke.Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.The risk of arterial thromboembolic complications in COC users increases with:• increasing age• smoking (women over 35 years should be strongly advised not to smoke if they wish to use a COC)• dyslipoproteinemia• hypercholesterolemia• hypertension• valvular heart disease• migraine• atrial fibrillation• obesity (body mass index over 30kg/m2)• diabetesb. Venous Thrombosis and ThromboembolismEpidemiological studies have shown that the incidence of venous thromboembolism (VTE) in users of oral contraceptives with low estrogen content (<50 mcg ethinylestradiol) ranges from about 20 to 40 cases per 100,000 women-years, but this risk estimate varies according to the progestogen. This compares with 5 to 10 cases per 100,000 women-years for non-users. The use of any COC carries an increased risk of VTE compared with no use.The excess risk of VTE is highest during the first year a woman ever uses a combined oral contraceptive. 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.The overall absolute risk (incidence) of VTE for levonorgestrel containing combined oral contraceptives with 30 micrograms ethinylestradiol is approximately 20 cases per 100,000 woman years of use. Epidemiological studies have also associated the use of combined COCs with an increased risk for myocardial infarction, transient ischaemic attack and for stroke.A two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. The risk for venous thromboembolic (VTE) complications in COCs users increases with: • Increasing age.• A positive family history (venous thromboembolism ever in a sibling or parent at 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.• Prolonged immobilization, major surgery, any surgery to the legs, or major trauma. In these situations, it is advisable to discontinue the pill (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilization. Antithrombotic treatment should be considered if the pills have not been discontinued in advance.• Obesity (body mass index over 30 kg/m2).• Recent delivery or second trimester abortion (see section 4.2).The risk of arterial thromboembolic complications or of a cerebrovascular accident in COC users increases with:• increasing age• smoking (women over 35 years should be strongly advised not to smoke if they wish to use a COC)• dyslipoproteinemia• hypertension• migraine• valvular heart disease• atrial fibrillation• obesity (body mass index over 30kg/m2)The presence of one serious or multiple risk factors for venous or arterial disease, respectively, can also constitute a contra-indication.There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in the onset or progression of venous thrombosis.The Health Care Practitioner should warn the patient to contact their physician immediately if they experience possible symptoms of thrombosis and discontinue the COC promptly.Extremely rarely, thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal, retinal veins and arteries, in contraceptive pill users. There is no consensus as to whether the occurrence of these events is associated with the use of hormonal contraceptives. Symptoms of venous or arterial thrombotic/thromboembolic events or of a cerebrovascular accident can include: • unusual 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• 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' abdomenThe increased risk of thromboembolism in the puerperium must be considered (see section 4.6).Other medical conditions which have been associated with adverse vascular events include diabetes mellitus, systemic lupus erythematosus, hemolytic uremic syndrome and 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, hyperhomocysteinemia, antithrombin-III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).c. Cerebrovascular DiseaseOral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (> 35 years), hypertensive women who also smoke. Hypertension has been found to be a risk factor for both users and nonusers, for both types of strokes, while smoking appears to increase the risk for hemorrhagic stroke. Transient ischaemic attacks have also been associated with oral contraceptive use. COC users with migraine (particularly migraine with aura) may be at increased risk of stroke.
2. Carcinoma of the Reproductive Organs
a. Cervical cancerThe most important risk factor for cervical cancer is persistent human papilloma virus infection.An increased risk of cervical cancer in long-term users of COCs has been reported in some epidemiological studies, but there continues to be controversy about the extent to which this finding is attributable to the confounding effects of sexual behaviour and other factors such as human papilloma virus (HPV).b. Breast cancerA 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 COCs. The increased risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC 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 COC users, the biological effects of COCs or a combination of both. Breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.
3. Hepatic Neoplasia/Liver Disease
In rare cases, benign liver tumors, and even more rarely, malignant liver tumors have been reported in users of COCs. In isolated cases, these tumors have lead to life-threatening intra abdominal haemorrhages. A hepatic tumor should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal hemorrhage occur in women taking COCs.Studies have shown an increased risk of developing hepatocellular carcinoma and hepatic adenoma in long-term oral contraceptive users, however, these cancers are extremely rare. Women with a history of COC-related cholestasis and women who develop cholestasis during pregnancy are more likely to develop cholestasis with COC use. Such patients who use COCs should be carefully monitored, and COC use should be discontinued if cholestasis recurs.Hepatocellular injury has been reported with COC 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 COC, 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 COC use until liver function has returned to normal.
4. Other Conditions
a. 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.
b. Gallbladder Disease
An increased relative risk of gallbladder disease in users of oral contraceptives and estrogens has been reported in some studies.
c. 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 μg) may create a state of hyperinsulinism. Women with impaired glucose tolerance or diabetes mellitus should be carefully observed while taking oral contraceptives, particularly in the early stage of COC use. However there is no evidence for a need to alter the therapeutic regimen in diabetics using low-dose COCs.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.Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.Some progestins may elevate low-density lipoproteins (LDL) levels and may render the control of hyperlipidemias more difficult. Non hormonal contraception should be considered in women with uncontrolled dyslipidemias.
Although small increases in blood pressure have been reported in many women taking COC's, clinically relevant increases are rare 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. Only in these rare cases an immediate discontinuation of COC use is justified. If, during the use of a COC in pre-existing hypertension, constantly elevated blood pressure values or a significant increase in blood pressure do not respond adequately to antihypertensive treatment, the COC must be withdrawn. Where considered appropriate, COC use may be resumed if normotensive values can be achieved with antihypertensive therapy.Women with a history of hypertension or hypertension-related diseases, or renal diseases should be encouraged to use another method of contraception. COC use is contraindicated in women with uncontrolled hypertension (see section 4.3).
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. f. Angioedema Exogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema.
g. Liver function
Acute or chronic liver dysfunction may necessitate the discontinuation of COC use until liver function returns to normal. Steroid hormones may be poorly metabolized in patients with impaired liver function. Recurrence of cholestatic jaundice and/or cholestasis-related pruritus which occurred during pregnancy or previous use of sex steroids necessitates the discontinuation of COCs.
h. 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.
i. 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.
j. St. John's wort
If combined oral contraceptives (COCs) and St. John's wort are used concomitantly, a non-hormonal back-up method of birth control is recommended (see section 4.5).
Diarrhoea and/or vomiting may reduce hormone absorption resulting in decreased serum concentration (see section 4.5).Worsening of Crohn's disease and of ulcerative colitis has been reported during COC use. Chloasma 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 COCs.The following conditions have been reported to occur or deteriorate with both pregnancy and COC use, but the evidence of an association with COC use is inconclusive: jaundice and/or pruritus related to cholestasis, gallstones, porphyria, systemic lupus erythematosus, haemolytic uremic syndrome, Sydenham´s chorea, herpes gestationis, otosclerosis-related hearing loss.
Physical Examination and Follow-up
Prior to the initiation or reinstitution of Ovranette 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). 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.Patients should be counselled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
The efficacy of COCs may be reduced, in the event of missed tablets, vomiting or diarrhoea or concomitant medication.
Reduced cycle control
With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. The type and dose of progestin may be important. Therefore, the evaluation of any irregular bleeding is only meaningful after an adaptation interval of about three cycles.If bleeding irregularities persist or 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.In some women withdrawal bleeding may not occur during the tablet-free interval. If the COC has been taken according to the directions described in section 4.2 it is unlikely that the woman is pregnant. However, if the COC has not been taken according to these directions prior to the first missed withdrawal bleed or if two withdrawal bleeds are missed, pregnancy must be ruled out before COC use is continued. Some women may encounter post-pill amenorrhea (possibly with anovulation) or oligomenorrhea, especially when such a condition was preexistent.This product contains lactose and sucrose. Patients with rare hereditary problems of galactose intolerance, fructose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption or sucrase-iosmaltase insufficiency should not take this medicine.