Summary of Product Characteristics Microgynon ED Fe

Transcription

1 Summary of Product Characteristics Microgynon ED Fe 1. NAME OF THE MEDICINAL PRODUCT Microgynon ED Fe coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One coated tablet contains 150 µg levonorgestrel and 30 µg ethinylestradiol Each hormone-free tablet contains 75 mg ferrous fumarate. See section 6.1 for a full list of the other ingredients. 3. PHARMACEUTICAL FORM Coated tablet 21 hormone-containing tablets: beige, round, convex, coated tablets 7 hormone-free tablets: brown, round, convex, coated tablets 4. CLINICAL PARTICULARS 4.1 Indications Oral contraception When making a decision on prescribing Microgynon ED Fe, consideration should be given to the current individual risk factors for the specific women, especially with respect to thromboembolisms (VTE). Likewise the VTE risk involved in using Microgynon ED Fe should be compared with that applicable to other combined hormonal contraceptives (CHCs) (see sections 4.3 and 4.4).

2 4.2 Dosage and administration route Administration route For ingestion Dosage The tablets should be taken every day at roughly the same time, if needed with some liquid, in the sequence shown on the blister pack. The tablets should be taken without any break. For 28 consecutive days one tablet should be taken daily. Tablet-taking should continue from the next pack the day after the last of the tablets from the previous pack is taken. As a rule, withdrawal bleeding occurs 2 to 3 days after the hormone-free tablets have been started. This may continue till after the new pack has been started on. Starting to take Microgynon ED Fe No previous use of hormonal contraceptives [in the previous month] Tablet-taking starts on the first day of the natural cycle (i.e. on Day 1 of menstruation). Additional contraceptive measures are recommended for the first 7 days if tablet-taking starts between Day 2 and Day 5. Switching from another combined hormonal contraceptive (COC, vaginal ring, transdermal patch) You should start taking Microgynon ED Fe preferably on the day after taking the last active tablet of the previous combined product (or on the day after the vaginal ring or patch was removed), but by no later than on the day after the usual tablet-free (ring- or patch-free) days, or on the day after the last hormone-free tablet of the previous combined product was taken. Switching from a progestogen-only preparation (pill, injection, implant) or an intrauterine system (IUS) It is possible to switch from the minipill on any day (switching from an implant or intrauterine system should be on the day of removal, and switching from an injectable should be at the time the next injection would have been due). In all these cases, however, additional contraceptives measures are needed for the first 7 days of tablet-taking. After an abortion in the first trimester Tablet-taking can start immediately. In this case it is not necessary to take any additional contraceptive measures. After delivery or an abortion in the second trimester See section 4.6 for use during lactation. Tablet-taking should start on Day 21 to Day 28 after a delivery or abortion in the second trimester. If tablet-taking starts later, an additional barrier method should be employed in the first seven days. If sexual intercourse has already taken place in the meantime, pregnancy must be ruled out before tablet-taking starts, or it is necessary to wait for the first menstruation.

3 What to do if a tablet is missed out Microgynon ED Fe contains a very low dose of the two hormones and therefore the range of contraceptive effect is very narrow when a tablet is missed out. If a tablet is taken within 12 hours of the usual time, the contraceptive effect is not jeopardized. In this case the missed tablet should be taken immediately. All the subsequent tablets should be taken at the usual time. If more than 12 hours have elapsed since the usual time, the contraceptive effect may be reduced. In principle 2 points must be borne in mind when tablets are missed out: 1. The taking of hormone-containing tablets should not be interrupted for more than 7 days. 2. The hormone-containing tablets should be taken for an uninterrupted period of 7 days to attain an adequate suppression of the hypothalamic-pituitary-ovarian-axis function. For everyday use it is therefore possible to give the following recommendations: Week 1: The user should take the last missed tablet as soon as she realizes she has forgotten it, even if this means taking two tablets at the same time. Tablet-taking should then continue at the usual time of day. In the next 7 days an additional barrier method, e.g. condom, should be used. If sexual intercourse has taken place in the previous 7 days, the possibility of pregnancy should be considered. The pregnancy risk is the higher the more tablets were missed out and the closer this is to the usual hormone-free-tablet period. Week 2 The user should take the last missed tablet as soon as she realizes she has forgotten it, even if this means taking two tablets at the same time. Subsequent tablets are then taken at the usual time of day. Provided the tablets were taken correctly on the last 7 days prior to the missed tablet, there is no need to take additional contraceptive measures. If this was not the case or if more than 1 tablet was missed out, it is recommended to take additional contraceptive measures for 7 days. Week 3 Full contraceptive protection is no longer afforded owing to the 7-day hormone-free-tablet period ahead. However it is possible to prevent a reduction in contraceptive effect by adjusting the regimen. If one of the following approaches is used, there is no need to take additional contraceptive measures, provided the tablets were taken correctly on the 7 days prior to the first tablet missed. If this is not the case, the user should proceed as described in paragraph 1 above and take additional contraceptive measures in the coming 7 days. 1. The user should take the last missed hormone-containing tablet as soon as possible, even if this means taking two tablets at the same time. Subsequent tablets are then taken at the usual time of day. Immediately after the hormone-containing tablets from the present blister pack have been used up, the next pack should be started with the hormone-containing tablets, i.e. without any hormone-free-tablet phase. It is unlikely for withdrawal bleeding to occur before the second pack is used up, but spotting or breakthrough bleeding might occur during this time.

4 2. It is also possible to stop taking hormone-containing tablets from the blister pack started. The user should then start by taking hormone-free tablets from the current blister pack, thus leaving a hormone-free-tablet period of 7 days (including the days she forgot to take the tablets). If the user forgot several tablets and withdrawal bleeding fails to occur in the first usual hormonefree-tablet phase, the possibility of pregnancy should be considered. Contraceptive protection is not impaired, if any of the hormone-free tablets are missed out. What to do in case of gastrointestinal disorders In the case of severe gastrointestinal disorders the active substances might not be completely absorbed; additional contraceptive measures should therefore be taken. If vomiting or severe diarrhea occurs within 3-4 hours of tablet taking, the same precautionary measures apply as in the case of a missed tablet. If the user does not wish to alter the tablettaking pattern, she should take a replacement tablet from another blister pack. Postponing the period and changing the day of week for the start of the period To delay menstruation, the user should continue with tablets from the next pack of Microgynon ED Fe, leaving out the hormone-free tablets. Withdrawal bleeding can thus be delayed as long as desired, but at most to the end of the second pack. During this time spotting or breakthrough bleeding may occur. After the hormone-free tablets have been taken in a regular fashion, Microgynon ED Fe can be continued as usual. To delay menstruation to another day of the week, the number of hormone-free tablets taken can be reduced by the appropriate number of days. The shorter the duration of the hormonefree-tablet phase, the higher is the likelihood that withdrawal bleeding will fail to occur and that breakthrough bleeding or spotting can occur during the use of the next pack (just like the case when delaying menstruation). 4.3 Contraindications Combined oral contraceptives (COCs) must not be used, if any of the following disorders apply. If any of these disorders occurs for the first time when using a COC, the product should be discontinued immediately. Presence of or risk for venous thromboembolism (VTE) Venous thromboembolism present VTE (also when being treated with anticoagulants) or a history of VTE (e.g. deep vein thrombosis [DVT] or pulmonary embolism ([PE]) Known hereditary or acquired predisposition towards venous thromboembolism, such as APC resistance (including Factor V Leiden), antithrombin III deficiency, Protein C deficiency or Protein S deficiency Major surgery involving prolonged immobilization (see section 4.4)

5 A high risk for venous thromboembolism on account of multiple risk factors (see section 4.4) Presence of or risk for arterial thromboembolism (ATE) Arterial thromboembolism present ATE, a history of ATE (e.g. myocardial infarction) or a disease in the prodromal stage (e.g. angina pectoris) Cerebrovascular disease present stroke, a history of stroke or prodromal condition (e.g. transitory ischemic attack [TIA]) Known hereditary or acquired predisposition towards arterial thromboembolism, such as hyperhomocysteinemia and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant) A history of migraine with focal neurological symptoms A high risk for arterial thromboembolism on account of multiple risk factors (see section 4.4) or a serious risk factor such as: Diabetes mellitus with vascular damage Severe hypertension Severe dyslipoproteinemia Present or past pancreatitis, if accompanied by severe hypertriglyceridemia Present or past severe hepatic conditions, as long as the liver function readings have not returned to normal Present or past hepatic tumors (benign or malignant) Known or suspected sex-hormone-dependent malignant tumors (e.g. of the genital organs or breast) Undiagnosed vaginal bleeding Amenorrhea of unknown cause Hypersensitivity to the active ingredients levonorgestrel and ethinylestradiol or any other ingredients specified in section Special warnings and precautions for use Warnings The suitability of Microgynon ED Fe should be discussed with the woman, if any of the conditions or risk factors listed below should apply. If any of the conditions or risk factors deteriorates or occurs for the first time, the user should be advised to contact her physician in order to decide whether the use of Microgynon ED Fe should be discontinued. Risk for venous thromboembolism (VTE) The use of any combined hormonal contraceptive (CHC) constitutes an enhanced risk for venous thromboembolism (VTE) as compared with non-use. The decision to use Microgynon ED Fe should only be made after talking to the woman, and it must be ensured that she understands the following: - the risk for VTE when using Microgynon ED Fe, - how her present individual risk factors impinge on this risk,

6 - and that her risk for VTE is highest in the very first year of use. There are also indications that the risk is higher, if the use of a CHC is restarted after a break of 4 weeks or more. Roughly two out of 10,000 women not using a CHC and who are not pregnant, suffer a VTE in the course of one year. In individual women the risk may be much higher, depending on the risk factors involved (see below). Roughly six 1 out of 10,000 women using a CHC containing levonorgestrel suffer a VTE in the course of one year. The number of cases of VTE per annum is lower with low-dosed CHCs than the number to be expected during pregnancy or in the period after childbirth. One to two percent of VTE cases are lethal. Annual number of cases of VTE events per 10,000 women Number of VTE events Non-users of CHCs (2 events) Users of CHCs containing levonorgestrel (5-7 events) In extremely rare cases there have been reports of users of CHCs suffering a thrombosis in other blood vessels, e.g. in veins or arteries of the liver, mesentery, kidneys, brain or retina. 1 Mean of the range 5-7 per 10,000 women years, based on a relative risk for CHCs containing levonorgestrel as compared to non-use at 2.3 to 3.6

7 Risk factors for VTE The risk for venous thromboembolic complications among users of CHCs may be greatly enhanced, if additional risk factors are present in the user, especially when multiple risk factors apply (see table). Microgynon ED Fe is contraindicated in women with multiple risk factors applying simultaneously that in total constitute a high risk for venous thrombosis (see section 4.3). If a woman demonstrates more than one risk factor, it is possible that the enhanced risk exceeds the sum of the individual factors. In such a case her overall risk for VTE must be considered. If the risk/benefit ratio is deemed to be unfavorable, a CHC should not be prescribed (see section 4.3). Table: Risk factors for VTE Risk factor Obesity (body-mass index above 30 kg/m²) Prolonged immobilization, major surgery, any surgery to the legs or hip, neurosurgery or serious injury Remarks The risk rises significantly with increasing BMI. Especially important if multiple risk factors apply. In these cases it is advisable to interrupt tablettaking (at least four weeks prior to scheduled surgery) and only to resume tablet-taking two weeks after complete mobilization. A different method of contraception should be used to prevent an unwanted pregnancy. Note: Transient immobilization including air flights of more than four hours may likewise constitute a risk factor for VTE, especially among women with other risk factors. A family history (any venous thromboembolism in a sibling or parent, especially at a relatively young age, e.g. younger than 50 years). Other conditions that are associated with a VTE. Increasing age Anticoagulation treatment should be considered, if Microgynon ED Fe was not discontinued in advance. If a genetic predisposition is suspected, the woman should be referred to a specialist before any decision on the use of a CHC is taken. Cancer, systemic lupus erythematosus; hemolytic uremic syndrome; chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell disease Especially older than 35 years

8 There is no consensus as to the possible role of varices and superficial thrombophlebitis concerning the onset or progression of venous thrombosis. The enhanced risk for a thromboembolism during pregnancy and especially during the six weeks of the puerperium should be taken into account (see section 4.6 for information on Pregnancy and lactation ). Symptoms of a VTE (deep vein thrombosis and pulmonary embolism) If symptoms occur the user should be advised to seek immediate medical help and to inform the medical professional staff that she is using a CHC. In the case of a deep vein thrombosis (DVT) the following symptoms may occur: - Unilateral swelling of a leg and/or foot or along a leg vein; - Pain or pressure sensation in a leg, possibly only noticed when standing or walking; - Warmth in the leg affected; reddened or pale skin on the leg. In the case of a pulmonary embolism (PE) the following symptoms may occur: - Sudden occurrence of unexplained shortness of breath or rapid breathing; - Sudden coughing bout, possibly in conjunction with hemoptysis; - Stabbing pain in the chest; - Severe obnubilation or dizziness; - Rapid or irregular heart beat. Several of these symptoms (e.g. shortness of breath, coughing ) are unspecific and may be misdiagnosed as frequently occurring or less serious events (e.g. respiratory infections). Other signs of an occluded vessel may be sudden pain or swelling and slightly cyanose discoloration of a limb. If the vessel occlusion occurs in the eye, the symptoms may be painless blurred vision ranging to loss of vision. In many cases the loss of vision occurs very suddenly. Risk for arterial thromboembolism (ATE) Epidemiological studies have linked the use of CHCs to an enhanced risk for arterial thromboembolism (myocardial infarction) or apoplectic insult (e.g. transitory ischemic attack, stroke). Arterial thromboembolic events may be lethal. Risk factors for ATE The risk for arterial thromboembolic complications or an apoplectic insult in users of CHCs is higher in women with risk factors (see table). Microgynon ED Fe is contraindicated in women who demonstrate one serious or several risk factors for an ATE which expose them to a higher risk for an arterial thrombosis (see section 4.3). If a woman demonstrates more than one risk factor, it is possible that the increased risk is higher than the sum of the individual factors. In this case the overall risk must be considered. If the risk/benefit ratio is unfavorable, a CHC should not be prescribed (see section 4.3).

9 Table: Risk factors for ATE Risk factor Increasing age Smoking Hypertension Obesity (body mass index above 30 kg/m²) Family history (any arterial thromboembolism in a sibling or parent, especially at a relatively young age, i.e. younger than 50 years). Migraine Other conditions linked to undesired vascular events Remarks Especially older than 35 years Women should be advised not to smoke, if they wish to use a CHC. Women over the age of 35 who continue to smoke are urgently advised to use a different method of contraception. The risk rises significantly with increasing BMI. Particularly important in women with additional risk factors. If a genetic predisposition is suspected, the woman should be referred to a specialist before any decision on the use of a CHC is taken. Increased frequency or severity of migraine when on CHCs (which may precede a cerebrovascular event) may be a reason for dropping the CHC immediately. Diabetes mellitus, hyperhomocysteinemia, mitral valve disease and atrial fibrillation, dyslipoproteinemia and systemic lupus erythematosus. Symptoms of an ATE If symptoms occur, the user should be advised to seek immediate medical help and to inform the medical professional staff that she is using a CHC. The following symptoms may occur in the case of an apoplectic insult: - Sudden numbness or weakness in the face, arm or leg, especially unilaterally; - Sudden difficulty in walking, dizziness, loss of balance or coordination problems; - Sudden confused state, difficulty in articulating or understanding; - Sudden visual impairment in one or both eyes; - Sudden severe or persisting headache without a known cause; - Loss of consciousness or fainting with or without a seizure. Transient symptoms point to a transitory ischemic attack (TIA). The following symptoms may occur in the case of myocardial infarction (MI): - Pain, unease, pressure, heavy, crushed or bloated feeling in the chest, arm or below the sternum; - Complaints that radiate into the back, jaw, neck, arm or stomach;

10 - Bloated feeling, indigestion or suffocating feeling; - Sweating, nausea, vomiting or dizziness; - Extreme weakness, anxiety state or shortness of breath; - Rapid or irregular heart beat. Tumors Several epidemiological studies indicate that the long-term use of COCs is associated with an enhanced risk for cervical cancer. There is still no consensus as to what extent this finding is due to sexual behavior and other factors, such as human Papilloma virus (HPV). A meta-analysis of 54 epidemiological studies showed that present users of a COC demonstrate a slightly enhanced risk for breast cancer (RR = 1.24). This enhanced risk gradually diminishes within ten years of cessation of COC use. Since breast cancer is relatively rare among women under the age of 40, the number of additional cases of breast cancer in any-time or current users of oral contraceptives is small in comparison to the overall risk of developing breast cancer. These studies failed to show any causes. The enhanced risk observed may be due to an early diagnosis of breast cancer among users, the biological effects of the COC or a combination of either factor. The tumors diagnosed in users appear to be at an earlier clinical stage than those diagnosed among non-users. In rare cases benign hepatic tumors have been observed among users of COCs, and in even rarer cases malignant ones. In isolated cased these tumors led to life-threatening abdominal hemorrhages. A liver 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 oral contraceptives. Other diseases Women with hypertriglyceridemia or a corresponding family history may run a higher risk of developing pancreatitis when taking COCs. Although in many women using combined oral contraceptives blood pressure was seen to be slightly higher, clinically significantly raised blood pressure is rare. Only in such rare instances is it justified to discontinue the COC immediately. So far there has been no proof of a systemic link between the use of COCs and clinical hypertension. If in the case of pre-existing hypertension with simultaneous use of an oral contraceptive a persistently enhanced blood pressure comes about or blood pressure rises significantly and antihypertensive treatment fails, the COC must be discontinued. If considered appropriate, the use of the COC may be resumed as soon as blood pressure readings have returned to normal under hypertensive treatment. The following clinical conditions are reported to have occurred or deteriorated both in pregnancy and when a COC is used. However, no correlation with the use of COCs could be proved: cholestatic icterus and/or pruritus, cholelithiasis, porphyria, systemic lupus erythematosus; hemolytic uremic syndrome; Sydenham s chorea; herpes gestationis; otosclerosis-related hearing loss, depressive moods. In women with hereditary angioedema, any exogenous estrogens may trigger or exacerbate the symptoms of angioedema.

11 Acute or chronic hepatic function disturbances may necessitate an interruption in COC use until the hepatic function readings have returned to normal. Likewise the recurrence of a cholestatic icterus and/or cholestasis-conditioned pruritus that appeared in a previous pregnancy or during earlier use of steroid sex hormones necessitate the discontinuation of the COC. Although COCs may have an influence on peripheral insulin resistance and glucose tolerance, there is no evidence to suggest any need to change the regimen for diabetics on low-dosed COCs. Diabetics should, however, be carefully monitored, especially in the initial phase of COC use. There have been reports of deterioration in endogenous depression, epilepsy, Crohn s disease and colitis ulcerosa among COC users. Chloasma may occasionally occur during the use of a COC, especially among women with a history of chloasma gravidarum. Users with this predisposition should therefore avoid direct sunlight or ultraviolet light when using a COC. This drug contains lactose and sucrose. Patients with the rare hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorbtion, who maintain a lactose-free diet, should take these amounts into consideration. Medical examination/checkups A detailed anamnesis (including family history taking) must be conducted prior to the first treatment or any renewed treatment with Microgynon ED Fe, and pregnancy must be ruled out. Blood pressure should be measured and a physical examination should be conducted, bearing in mind the Contraindications (see section 4.3) and Warnings (see section 4.4). It is important to point to the information on venous and arterial thromboses, including the risk occasioned by Microgynon ED Fe in comparison with other CHC, the symptoms of VTE and ATE, the known risk factors, and what to do in case a thrombosis is suspected. The user should be instructed to read the package insert and to observe the advice given there. The frequency and type of examination should follow the usual examination guidelines and should be adapted to the specific woman concerned. The user should be informed that taking oral contraceptives does not afford any protection against HIV infection (AIDS) and other sexually transmitted diseases. Reduced efficacy The efficacy of a COC may be impaired, if tablets are forgotten, in the case of vomiting or diarrhea, or when certain other medicines are taken at the same time. Irregular bleeding With all COCs there may be irregular bleeding (spotting or breakthrough bleeding), especially in the first few months of use. For this reason it is sensible to wait about three cycles before assessing such intermenstrual bleeding. In more than 50 % of users of oral contraceptives

12 containing ethinylestradiol/levonorgestrel, bleeding (spotting or breakthrough bleeding) has been observed during the first six cycles of the product. If this irregular bleeding pattern persists or reappears after previously regular cycles, nonhormonal causes should be taken into account and appropriate diagnostic measures should be started to rule out any malignancies or pregnancy. Curettage may be necessary. It is possible for some users not to have any withdrawal bleeding during the hormone-free-tablet phase. Pregnancy is unlikely, if the COC was taken as described in section 4.2. It tablet-taking was irregular prior to the first non-occurrence of withdrawal bleeding, or if withdrawal bleeding fails to occur a second time, pregnancy must be definitely ruled out before continuing with the use of the COC. 4.5 Drug interactions or other interactions Note: The professional datasheets of any medicinal products prescribed concomitantly should be consulted for possible interactions. Influence of other medicinal products on Microgynon ED Fe Interactions may occur with drugs that induce microsomal enzymes. This may lead to an enhanced clearance of sex hormones and breakthrough bleeding and/or contraceptive failure. Women being treated with such drugs should for the time being use a barrier method or other contraceptives methods in addition to the COC. The barrier method should be used throughout the duration of concomitant use of the medicine and up to 28 days after such treatment ends. If any of such drugs need to be taken beyond the end of a COC blister pack, the next blister pack of the COC should be started straight away without taking any hormone-free tablets. Reduced absorption: Drugs which enhance gastrointestinal motility, such as metoclopramide, can reduce the absorption of hormones. Substances that enhance COC clearance (reduced COC efficacy by virtue of enzyme induction), such as: Phenytoin, barbiturates, primidone, carbamazepine, rifampicin and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin. Herbal remedies containing St. John s wort (Hypericum perforata) should not be used concomitantly with Microgynon ED Fe tablets, since they can reduce the contraceptive effect of Microgynon ED Fe. Breakthrough bleeding and unwanted pregnancies have been reported. The enzyme reducing effect can persist up to two weeks after discontinuing treatment with St. John s wort.

13 Substances with diverse effects on the clearance of COC, such as: ritonavir, nevirapine HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors may increase or decrease plasma levels of estrogens and progestogens when administered concomitantly with a COC.. In some cases these changes may be clinically relevant. Substances that increase COC active substance levels (enzyme inhibitors): Strong and moderate CYP3A4 inhibitors, such as azole antimycotic agents (e.g. itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice may increase plasma levels of estrogen or progestogen or both. In the case of etoricoxib in doses of 60 to 120 mg/die it was demonstrated that it increased plasma levels of ethinylestradiol by a factor of 1.4 or 1.6, if a COC containing 35 micrograms of ethinylestradiol was administered concomitantly. Influence of COCs on other medicinal products Troleandomycin can, if used simultaneously with a COC, increase the risk of intrahepatic cholestasis. COCs can influence the metabolism of other drugs. Enhanced plasma levels of cyclosporine have been observed when taken concomitantly with an oral contraceptive. COCs can induce the metabolism of lamotrigine and thus lead to a lamotrigine plasma level below the therapeutic threshold. In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1 and CYP1A2 and a mechanism-based inhibitor of CYP3A4/5, CYP2C8 und CYP2J2. In clinical studies the use of an oral contraceptive containing ethinylestradiol did not lead to an enhanced or even a slightly higher plasma level of CYP3A4 substrates (e.g. midazolam), while the plasma levels of CYP1A2 substrates were in part slightly (e.g. theophylline) or moderately (e.g. melatonin and tizanidine) increased. Note: The professional datasheets of any medicinal products prescribed concomitantly should be consulted for possible interactions. Influence of COCs on other medicinal products Troleandomycin can, if used simultaneously with a COC, increase the risk of intrahepatic cholestasis. COCs can influence the metabolism of other drugs. Enhanced plasma levels of cyclosporine have been observed when taken concomitantly with an oral contraceptive. COCs can induce the metabolism of lamotrigine and thus lead to a lamotrigine plasma level below the therapeutic threshold.

14 In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1 and CYP1A2 and a mechanism-based inhibitor of CYP3A4/5, CYP2C8 und CYP2J2. In clinical studies the use of an oral contraceptive containing ethinylestradiol did not lead to an enhanced or even a slightly higher plasma level of CYP3A4 substrates (e.g. midazolam), while the plasma levels of CYP1A2 substrates were in part slightly (e.g. theophylline) or moderately (e.g. melatonin and tizanidine) increased. Laboratory tests The use of steroid contraceptives may influence the findings of certain laboratory tests, including the biochemical parameters of hepatic, thyroid, adrenal and renal functions as well as plasma levels of the (vector) proteins (e.g. of corticosteroid-binding globulin and of lipid/lipoprotein fractions), the carbohydrate metabolism parameters as well as coagulation and fibrinolysis parameters. As a rule, however, these changes remain within the normal range. 4.6 Fertility, pregnancy and lactation Microgynon ED Fe is not indicated during pregnancy. If pregnancy occurs while Microgynon ED Fe is being used, the drug should be discontinued immediately. In most epidemiological studies there was no evidence either of an enhanced risk of malformations among children whose mothers had taken oral contraceptives prior to pregnancy, or of any teratogenic effect with accidental use of combined oral contraceptives in early pregnancy. COCs can impair lactation because they can reduce the amount and composition of the mother s milk. The use of COCs is therefore not advised as long as the mother has not fully weaned off the child. Small amounts of the contraceptive steroids or their metabolites can pass into the mother s milk. These amounts could be detrimental to the child. 4.7 Effects on the ability to drive and operate machines Microgynon ED Fe has no or only a negligible effect on the ability to drive or operate machines. 4.8 Side effects The most common side effects of the use of combined oral contraceptives containing EE/LNG are headache, spotting and intermenstrual bleeding. Other side effects reported by users of oral combined hormonal contraceptives containing EE/LNG, to which group Microgynon ED Fe belongs, are:

15 Organ system Eye disorders Gastrointestinal tract disorders Immune system disorders Common (>1/100) Nausea, abdominal pain Uncommon (>1/1000, <1/100) Vomiting, diarrhea Rare ( 1/10,000 to <1/1,000) Poor tolerance of contact lenses Hypersensitivity Tests Weight gain Weight loss Metabolic and nutritional disorders Nervous system disorders Psychiatric disorders Genital organ and breast disorders Disorders of the skin and subcutaneous tissue Vascular disorders Headache Depressive mood, mood swings Breast tenderness, breast pain Fluid retention Migraine Reduced libido Breast engorgement Exanthema, urticaria Increased libido Breast secretion, vaginal discharge Erythema nodosum, Erythema multiforme Venous thromboembolism (VTE) Arterial thromboembolism (ATE) *The most suitable MedDRA term (version 7.0) is listed to describe a certain side effect. Synonyms or related terms are not listed, but should be taken into account. Description of selected side effects In users of CHC an enhanced risk for arterial and venous thrombotic and thromboembolic events including myocardial infarction, stroke, transitory ischemic attacks, venous thrombosis and pulmonary embolism has been observed; these are dealt with in greater detail in section 4.4. The following serious side effects have been reported by women using combined oral contraceptives and are described in section 4.4: - Venous thromboembolic disorders; - Arterial thromboembolic disorders;

16 - Cervical cancer; - Hypertension; - Hypertriglyceridemia; - Effects on peripheral insulin resistance and glucose tolerance; - Hepatic tumors; - Impaired hepatic function; - Chloasma; Crohn s disease, Colitis ulcerosa; - Epilepsy; - Migraine; - Endometriosis, uterine myoma; - Porphyria; - Systemic lupus erythematosus - Herpes gestationis; - Sydenham s chorea; - Hemolytic-uremic syndrome; - Cholestatic icterus; - Otosclerosis. The frequency of breast cancer diagnosis is slightly enhanced among OC users. Since breast cancer rarely develops among women below the age of 40, the risk of developing breast cancer is low in relation to the overall risk. There is no evidence of a causal link to the use of COCs. See sections 4.3 and 4.4 for further details. In women with hereditary angioedema, any exogenous estrogens may trigger or exacerbate the symptoms of angioedema. 4.9 Overdose There have been no reports of serious side effects through an overdose. Symptoms that can be caused by an overdose are nausea, vomiting and slight vaginal bleeding in young girls. There is no antidote. Treatment will be symptomatic. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic category: Progestogens and estrogens, fixed combinations, ATC code: G03AA07 The contraceptive effect of a COC is an interaction of various factors. The most important of these factors are the inhibition of ovulation and the change to the cervical mucus. Clinical trials were conducted on 2,498 women aged between 18 and 40. The Pearl index calculated from these trials was 0.69 (95% confidence interval 0.30 to 1.36) based on 15,026 cycles.

17 5.2 Pharmacokinetic properties Levonorgestrel Absorption: Following oral administration, levonorgestrel is quickly and completely absorbed. Levonorgestrel serum levels peaked at roughly 2.3 ng/ml about 1.3 hours after ingestion. Bioavailability is almost 100 %. Distribution Levonorgestrel is bound to serum albumin and to sex hormone binding globulin (SHBG). Only approx. 1.1 % of the overall serum concentration is in the form of free steroid, approx. 65 % is bound specifically to SHBG and roughly 35 % is bound nonspecifically to albumin. The ethinylestradiol-induced increase in SHBG influences the relative distribution of levonorgestrel in various protein fractions. The induction of the binding protein causes an increase in the SHBGbound fraction and a decrease in the albumin-bound fraction. The apparent volume of distribution of levonorgestrel is about 129 l after single administration. Biotransformation Levonorgestrel is almost completely metabolized. The main metabolites in the plasma are the unconjugated and conjugated forms of 3α, 5β-tetrahydrolevonorgestrel. Going by in-vitro and invivo studies, CYP3A4 is the main enzyme involved in the metabolism of levonorgestrel. The metabolic serum clearance rate is roughly 1.0 ml/min/kg. Elimination Levonorgestrel serum levels decrease in two phases. The terminal phase is characterized by a half-life of approximately 25 hours. Levonorgestrel is not excreted in unchanged form. Its metabolites are excreted at a urinary to biliary ratio of about 1:1. The half-life of metabolite excretion is about 1 day. Steady-state conditions Following continuous use of Microgynon ED Fe levonorgestrel serum levels increase about threefold, reaching steady-state conditions during the second half of a treatment cycle. Levonorgestrel pharmacokinetics is influenced by SHBG serum levels, which are increased about 1.5- to 1.6-fold with estradiol use. For this reason the clearance rate from serum and the distribution volume are slightly lower under steady-state conditions (0.7 ml/min/kg and 100 l respectively). Ethinylestradiol Absorption: Following oral administration, ethinylestradiol is quickly and completely absorbed. Peak serum concentrations of about 50 pg/ml are reached within around 1-2 hours of tablet ingestion. During absorption and first liver passage, ethinylestradiol is metabolized extensively, resulting in a mean oral bioavailability of about 45% (interindividual variability roughly 20-65%). Distribution Ethinylestradiol is highly but non-specifically bound to serum albumin (approximately 98%), and induces an increase in the serum levels of SHBG. The apparent distribution volume of ethinylestradiol is about l/kg.

18 Biotransformation Ethinylestradiol is mainly metabolized by enteral and hepatic first-pass metabolism. Ethinylestradiol and its oxidative metabolites are mainly conjugated with glucuronides or sulfates. The metabolic clearance rate is stated to be about ml/min/kg. Elimination Ethinylestradiol serum levels decrease in two phases characterized by half-lives of about 1 hour and hours, respectively. Ethinylestradiol is not excreted in unchanged form. Its metabolites are excreted at a urinary to biliary ratio of 4:6. The half-life is roughly 1 day Steady-state conditions Ethinylestradiol serum levels roughly double with continuous use of Microgynon ED Fe. Owing to the daily use and the variable half-life of the terminal phase of clearance from serum, steadystate serum clearance is reached after about one week. 5.3 Preclinical safety data Preclinical data (on overall toxicity, genotoxicity, cancerogenic potential and reproduction toxicity) provided no evidence of effects beyond those already known from the hormone profiles of ethinylestradiol and levonorgestrel. However, it should be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumors. 6. PHARMACEUTICAL PARTICULARS 6.1 List of other ingredients* ) Hormone-containing tablets: Tablet core: Lactose monohydrate, maize starch, povidone K25, talc, magnesium stearate (Ph.Eur.) [vegetable] Tablet coating: Sucrose, povidone 700,000, macrogol 6000, calcium carbonate, talc, glycerol 85%, montanglycol wax, titanium dioxide (E171), ferric hydroxide oxide x H 2 0 (E172) Hormone-fee tablets: Tablet core: Ferrous fumarate, lactose monohydrate, maize starch, povidone K25, talc, magnesium stearate (Ph.Eur.) [vegetable] Tablet coating: Sucrose, povidone 700,000, macrogol 6000, calcium carbonate, talc, titanium dioxide (E171), ferric hydroxide oxide x H 2 0 (E172), montanglycol wax

19 6.2 Incompatibilities Not applicable. 6.3 Shelf-life 5 years 6.4 Special precautions for storage Do not store above 25 C. 6.5 Nature and contents of container Each blister strip contains 21 beige hormone-containing tablets and 7 brown hormone-free tablets. Microgynon ED Fe is available in packs containing 3x28 tablets in blister strips (PVC/aluminum). 6.6 Special precautions for disposal Tablets no longer required should not be disposed of via the local sewage system. Please take the packs to your pharmacist or obtain advice from your pharmacist on suitable disposal channels. Such measures are to protect the environment. 7. MARKETING AUTHORISATION HOLDER / SUPPLIER* ) Jenapharm GmbH & Co. KG Otto-Schott-Strasse Jena Germany 8. MARKETING AUTHORISATION NUMBER / WHO REFERENCE NUMBER (PREQUALIFICATION PROGRAMME)* ) / RH DATE OF MARKETING AUTHORISATION/RENEWAL OF THE AUTHORISATION 27/05/2005

20 10. INFORMATION STATUS March SALES RESTRICTIONS Prescription mandatory * ) The only difference between the SRA-approved and the WHO prequalified product is the composition and the colour of the seven hormone-free tablets in each blister. For further details see part 1 of this WHOPAR.