![052015 1/15 SUMMARY of PRODUCT CHARACTERISTICS 1 NAME of the MEDICINAL PRODUCT [XXX] 20 Micrograms/150 Micrograms Film-Coated Ta](http://data.docslib.org/img/50138b947b175a9b52e83a851391b834-1.webp)
mibe GmbH Arzneimittel DE/H/2745/002/DC 0014
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
[XXX] 20 micrograms/150 micrograms film-coated tablets [XXX] 30 micrograms/150 micrograms film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
For [XXX] 20 micrograms/150 micrograms film-coated tablets Each film-coated tablet contains 20 mcg ethinylestradiol and 150 mcg desogestrel.
For [XXX] 30 micrograms/150 micrograms film-coated tablets Each film-coated tablet contains 30 mcg ethinylestradiol and 150 mcg desogestrel.
Excipients with known effect:
For [XXX] 20 micrograms/150 micrograms film-coated tablets lactose monohydrate 47.24 mg (see section 4.4).
For [XXX] 30 micrograms/150 micrograms film-coated tablets lactose monohydrate 47.23 mg (see section 4.4).
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Film-coated tablet. White, biconvex, round film-coated tablets with embossing.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Oral contraception.
The decision to prescribe [XXX] should take into consideration the individual woman’s current risk factors, particularly those for venous thromboembolism (VTE), and how the risk of VTE with [XXX] compares with other CHCs (see sections 4.3 and 4.4).
4.2 Posology and method of administration
How to take [XXX] The tablets are to be taken every day, where possible at the same time of day, with sufficient liquid in the order indicated on the blister pack. One tablet is to be taken daily on 21 consecutive days. Before every additional blister pack a 7-day administration-free interval is to be observed in which withdrawal bleeding usually occurs. This normally begins 2 to 3 days after the last tablet dose and may persist while the next blister pack is already being started.
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How to start [XXX] Women who have not taken hormonal contraceptives in the last month Tablet administration is to begin on the first day of the normal menstrual cycle (i.e. on the first day of the period). Administration may be started as from day 2 to 5, with the additional use of a mechanical contraceptive being recommended during the first 7 days of tablet administration in the first cycle.
Switching from a combined hormonal contraceptive (combined oral contraceptive [COC], vaginal ring or transdermal patch) Administration of [XXX] is preferably to be started the day after last administration of the last tablet containing active substance of the combined oral contraceptive taken previously, but at the latest the day after the usual administration-free interval or the placebo phase of the previous combined oral contraceptive. If a vaginal ring or a transdermal patch has been used to date, administration of [XXX] should preferably be started on the day of removal, but at the latest when the next use would be due.
Switching from a gestagen monopreparation (minipill, injection, implant) or a gestagen-releasing intrauterine system (IUS) Switching from the minipill may take place on any day, from an implant or an IUS on the day of removal and from an injection preparation when the next injection would be due. A mechanical contraceptive is to be used for the first 7 days of tablet administration in all these cases.
After an abortion in the first trimester Administration of [XXX] may be started immediately. Additional contraceptive measures are not necessary in this case.
After delivery or an abortion in the second trimester For breast-feeding, see section 4.6. The use of [XXX] should be started between day 21 and 28 after delivery or second-trimester-abortion in the second trimester. If started later, a mechanical contraceptive is also to be used for the first 7 days of tablet administration. If sexual intercourse has taken place in the meantime, pregnancy is to be ruled out before the beginning of administration or the first period should be awaited.
Missed tablets If, within 12 hours after the usual administration time, it is noticed that a tablet has been missed, the tablet should be taken immediately. All subsequent tablets are then to be taken at the usual time of day. Contraceptive protection is then not impaired.
If tablets have been missed for more than 12 hours after the usual time of administration, full contraceptive protection may no longer exist.
The following two basic rules apply to the procedure for missed tablets:
1. Administration must not be interrupted for more than 7 days. 2. Regular administration for at least 7 days is required to suppress the hypothalamic-pituitary- ovarian axis effectively.
The following procedure may be recommended in daily practice:
Week 1 The missed tablet should be taken immediately as soon as the missed dose is noticed – even if this means that 2 tablets are to be taken at the same time. The following tablets should be taken at the usual time. Mechanical contraception, e.g. a condom, is also to be used for the next 7 days. If intercourse has already taken place in the previous 7 days, the possibility of a pregnancy must be taken into account. The more tablets have been missed and the closer to the regular administration-free interval, the greater the risk of pregnancy.
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Week 2 The missed tablet should be taken immediately after the missed dose is noticed – even if this means that 2 tablets are to be taken at the same time. The following tablets should be taken at the usual time. On condition that regular administration took place on the previous 7 days, no additional use of a mechanical contraceptive is required. If this was not the case or more than 1 tablet was missed, a mechanical contraceptive is also to be used for the next 7 days.
Week 3 In view of the imminent administration-free interval there is an increased risk of pregnancy which can, however, be reduced with appropriate adaptation of the method of administration. If one of the following two administration options is used, no additional contraceptive measures are required if administration took place regularly on the 7 days before the first missed tablet. Otherwise, the user must be instructed to follow the first of the two administration options and also use a mechanical contraceptive for the next 7 days.
1. The missed tablet should be taken immediately as soon as the missed dose is noticed – even if this means that 2 tablets are to be taken at the same time. The other tablets should be taken at the usual time. Administration of the tablets from the next blister pack is to be continued directly after the end of the current blister pack, i.e. without observing the administration-free interval. The usual withdrawal bleeding will probably not occur until this second blister pack is used up. Frequent breakthrough bleeding or spotting may, however, occur during tablet administration. 2. Alternatively the further administration of tablets from the current blister pack may be stopped. After an administration-free interval of up to 7 days, including any days on which administration was missed administration is continued with tablets from the next blister pack.
If no withdrawal bleeding occurs after a missed dose in the next regular administration-free interval, the possibility of pregnancy should be considered.
Advice in case of gastro-intestinal complaints In the case of severe gastrointestinal complaints (e.g. vomiting or diarrhoea), absorption may be incomplete. Additional contraceptive precautions are then to be taken.
Where vomiting occurs within 3 to 4 hours after tablet administration a new (replacement) tablet should be taken as soon as possible. The new tablet should be taken within 12 hours of the usual time of tablet-taking if possible. If more than 12 hours elapse, the instructions under "Procedure for missed tablets", as set out in section “Missed tablets”, are to be followed. If the usual administration regime is to be followed, the additional tablet to be taken must be taken from another blister pack.
Postponing or delaying the menstruation Postponing the menstruation is not an indication for this preparation. To postpone menstruation in exceptional cases the user should continue with tablet administration from the next blister pack of [XXX] directly without an administration-free interval. Withdrawal bleeding may be postponed for as long as desired until the second blister pack has been used up. Breakthrough bleeding or spotting may occur frequently during this period. Administration of [XXX] may be continued as usual after the following regular 7-day administration-free interval.
The beginning of menstruation in the next cycle may be brought forward to another day of the week by shortening the administration-free interval as desired. The shorter the administration-free interval, the more unlikely it is for withdrawal bleeding to occur or the more frequently spotting or breakthrough bleeding may occur during administration of the next blister pack (as with postponement of menstruation).
4.3 Contraindications
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Combined hormonal contraceptives (CHCs) should not be used in the following conditions. Should any of the conditions appear for the first time during CHC use, the product should be stopped immediately.
- Hypersensitivity to any of the active substances or to any of the excipients listed in section 6.1 - Presence or risk of venous thromboembolism (VTE) - Venous thromboembolism – current VTE (on anticoagulants) or history of (e.g. deep venous thrombosis [DVT] or pulmonary embolism [PE]) - Known hereditary or acquired predisposition for venous thromboembolism, such as APC- resistance, (including Factor V Leiden), antithrombin-III-deficiency, protein C deficiency, protein S deficiency - Major surgery with prolonged immobilisation (see section 4.4) - A high risk of venous thromboembolism due to the presence of multiple risk factors (see section 4.4) - Presence or risk of arterial thromboembolism (ATE) - Arterial thromboembolism – current arterial thromboembolism, history of arterial thromboembolism (e.g. myocardial infarction) or prodromal condition (e.g. angina pectoris) - Cerebrovascular disease – current stroke, history of stroke or prodromal condition (e.g. transient ischaemic attack, TIA) - Known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant). - History of migraine with focal neurological symptoms. - A high risk of arterial thromboembolism due to multiple risk factors (see section 4.4) or to the presence of one serious risk factor such as: - diabetes mellitus with vascular symptoms - severe hypertension - severe dyslipoproteinaemia - current or previous pancreatitis, if associated with severe hypertriglyceridaemia - current or previous severe liver disease as long as abnormal liver function parameters exist - current or previous benign or malignant liver tumours - current or suspected sex hormone-dependent malignant diseases (e.g. of the genitals or breasts) - endometrial hyperplasia - unexplained vaginal bleeding.
4.4 Special warnings and precautions for use
WARNINGS If any of the conditions or risk factors mentioned below is present, the suitability of [XXX] should be discussed with the woman. In the event of aggravation, or first appearance of any of these conditions or risk factors, the woman should be advised to contact her doctor to determine whether the use of [XXX] should be discontinued.
Serious side-effects of combined hormonal contraceptives
Risk of venous thromboembolism (VTE)
The use of any combined hormonal contraceptive (CHC) increases the risk of venous thromboembolism (VTE) compared with no use. Products that contain levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. Other products such as [XXX] may have up to twice this level of risk. The decision to use any product other than one with the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with [XXX], how her current risk factors influence this risk, and that her VTE risk is highest in the first ever year of use. There is also some evidence that the risk is increased when a CHC is re-started after a break in use of 4 weeks or more.
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In women who do not use a CHC and are not pregnant about 2 out of 10,000 will develop a VTE over the period of one year. However, in any individual woman the risk may be far higher, depending on her underlying risk factors (see below). It is estimated1 that out of 10,000 women who use a CHC containing desogestrel between 9 and 12 women will develop a VTE in one year; this compares with about 62 in women who use a levonorgestrel-containing CHC.
In both cases, the number of VTEs per year is fewer than the number expected during pregnancy or in the postpartum period.
VTE may be fatal in 1-2% of cases.
Number of VTE events per 10,000 women in one year
Non-CHC user (2 events) Levonorgestrel-containing CHC Desogestrel-containing CHC (5-7 events) (9-12 events)
Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal or retinal veins or arteries.
Risk factors for VTE The risk for venous thromboembolic complications in CHC users may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see table).
[XXX] is contraindicated if a woman has multiple risk factors that put her at high risk of venous thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors – in this case her total risk of VTE should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed (see section 4.3).
Table: Risk factors for VTE Risk factor Comment
1 These incidences were estimated from the totality of the epidemiological study data, using relative risks for the different products compared with levonorgestrel-containing CHCs. 2 Mid-point of range of 5-7 per 10,000 WY, based on a relative risk for CHCs containing levonorgestrel versus non-use of approximately 2.3 to 3.6 052015 5/15 mibe GmbH Arzneimittel DE/H/2745/002/DC 0014
Obesity (body mass index over 30 kg/m²) Risk increases substantially as BMI rises. Particularly important to consider if other risk factors also present. Prolonged immobilisation, major surgery, any In these situations it is advisable to discontinue surgery to the legs or pelvis, neurosurgery, or use of the pill (in the case of elective surgery at major trauma least four weeks in advance) and not resume until two weeks after complete remobilisation. Another method of contraception should be used to avoid unintentional pregnancy.
Antithrombotic treatment should be considered if [XXX] has not been discontinued in advance. Note: temporary immobilisation including air travel >4 hours can also be a risk factor for VTE, particularly in women with other risk factors Positive family history (venous thromboembolism If a hereditary predisposition is suspected, the ever in a sibling or parent especially at a woman should be referred to a specialist for relatively early age e.g. before 50) advice before deciding about any CHC use. Other medical conditions associated with VTE Cancer, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis) and sickle cell disease Increasing age Particularly above 35 years
There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in the onset or progression of venous thrombosis.
The increased risk of thromboembolism in pregnancy, and particularly the 6 week period of the puerperium, must be considered (for information on “Fertility, pregnancy and lactation” see section 4.6).
Symptoms of VTE (deep vein thrombosis and pulmonary embolism) In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.
Symptoms of deep vein thrombosis (DVT) can include: - unilateral swelling of the leg and/or foot or along a vein in the leg - pain or tenderness in the leg which may be felt only when standing or walking - increased warmth in the affected leg; red or discoloured skin on the leg.
Symptoms of pulmonary embolism (PE) can include: - sudden onset of unexplained shortness of breath or rapid breathing - sudden coughing which may be associated with haemoptysis - sharp chest pain - severe light headedness or dizziness - rapid or irregular heartbeat.
Some of these symptoms (e.g. “shortness of breath”, “coughing”) are non-specific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections).
Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of an extremity.
If the occlusion occurs in the eye symptoms can range from painless blurring of vision which can progress to loss of vision. Sometimes loss of vision can occur almost immediately.
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Risk of arterial thromboembolism (ATE)
Epidemiological studies have associated the use of CHCs with an increased risk for arterial thromboembolism (myocardial infarction) or for cerebrovascular accident (e.g. transient ischaemic attack, stroke). Arterial thromboembolic events may be fatal.
Risk factors for ATE The risk of arterial thromboembolic complications or of a cerebrovascular accident in CHC users increases in women with risk factors (see table). [XXX] is contraindicated if a woman has one serious or multiple risk factors for ATE that puts her at high risk of arterial thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors - in this case her total risk should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed (see section 4.3).
Table: Risk factors for ATE Risk factor Comment Increasing age Particularly above 35 years Smoking Women should be advised not to smoke if they wish to use a CHC. Women over 35 who continue to smoke should be strongly advised to use a different method of contraception. Hypertension Obesity (body mass index over 30 kg/m²) Risk increases substantially as BMI increases. Particularly important in women with additional risk factors. Positive family history (arterial thromboembolism If a hereditary predisposition is suspected, the ever in a sibling or parent especially at relatively woman should be referred to a specialist for early age e.g. below 50) advice before deciding about any CHC use. Migraine An increase in frequency or severity of migraine during CHC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation. Other medical conditions associated with adverse Diabetes mellitus, hyperhomocysteinaemia, vascular events valvular heart disease and atrial fibrillation, dyslipoproteinaemia and systemic lupus erythematosus
Symptoms of ATE In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.
Symptoms of a cerebrovascular accident can include: - sudden numbness or weakness of the face, arm or leg, especially on one side of the body - sudden trouble walking, dizziness, loss of balance or coordination - sudden confusion, trouble speaking or understanding - sudden trouble seeing in one or both eyes - sudden, severe or prolonged headache with no known cause - loss of consciousness or fainting with or without seizure.
Temporary symptoms suggest the event is a transient ischaemic attack (TIA).
Symptoms of myocardial infarction (MI) can include:
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- pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone - discomfort radiating to the back, jaw, throat, arm, stomach - feeling of being full, having indigestion or choking - sweating, nausea, vomiting or dizziness - extreme weakness, anxiety, or shortness of breath - rapid or irregular heartbeats.
The risk-benefit assessment must take account of the fact that adequate therapy of a disease reduces the associated thrombosis risk and that a pregnancy poses a higher risk of thrombosis than the administration of combined oral contraceptives.
Tumour diseases
Epidemiological studies indicate that long-term administration of oral contraceptives to women infected with the human papillomavirus (HPV) poses the risk of the development of cervical carcinoma. However, there is still disagreement about the extent to which this finding is influenced by other factors (such as numbers of sexual partners or use of mechanical contraceptives).
A meta-analysis of 54 epidemiological studies has shown that the relative risk of diagnosis of carcinoma of the breast in women who take combined oral contraceptives is slightly increased (RR = 1.24). After the withdrawal of combined oral contraceptives, the increased risk falls continuously and disappears within 10 years. Because carcinomas of the breast are rare before the 40th year of life, the additionally diagnosed number of carcinomas of the breast relative to the total risk of carcinomas of the breast is small in women who take or who have until recently taken a combined oral contraceptive. These studies provide no evidence of causality. The observed increase in risk may be attributable both to early detection in users of combined oral contraceptives and to biological effects of combined oral contraceptives or to both factors jointly. Carcinomas of the breast in women who have taken a combined oral contraceptive tended to be less advanced at the time of diagnosis than in women who have never taken a combined oral contraceptive.
In rare cases, the occurrence of benign and, even more rarely, malignant tumours of the liver has been reported during the use of combined oral contraceptives. In individual cases, these tumours have led to life-threatening intra-abdominal bleeding. In the event of severe pain in the epigastrium, enlargement of the liver or evidence of intra-abdominal bleeding during administration of combined oral contraceptives, a tumour of the liver must be investigated by differential diagnosis.
Other diseases
An increased risk of pancreatitis may be expected in women with existing or familial hypertriglyceridaemia who are receiving combined oral contraceptives.
Although a slight increase in blood pressure has been reported relatively frequently for the use of combined oral contraceptives, clinically relevant increased blood pressure values are rare. There is no confirmed link between administration of combined oral contraceptives and hypertension. If a clear increase in blood pressure nevertheless arises during administration of combined oral contraceptives, these should be withdrawn and antihypertensive therapy started. Recent administration of combined oral contraceptives may be considered as soon as blood pressure values have normalised under antihypertensive therapy.
The occurrence or aggravation of the following conditions has been reported both in pregnant women and during the use of combined oral contraceptives, but the available data do not allow clear causal conclusions: cholestatic jaundice and/or pruritus; cholelithiasis; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; chorea minor; herpes gestationis; otosclerosis-induced hearing loss.
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In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.
Acute and chronic disturbances of liver function may necessitate the withdrawal of combined oral contraceptives until liver function parameters have normalised again. In the event of recurrence of cholestatic jaundice which has occurred for the first time during pregnancy or during previous administration of sex steroid hormones, combined oral contraceptives must be withdrawn.
Although an influence on peripheral insulin resistance and glucose tolerance may occur during administration of combined oral contraceptives, a change in the therapeutic regime does not seem necessary. Nevertheless, women with diabetes who take combined oral contraceptives should be monitored closely.
Worsening of endogenous depression, epilepsy, Crohn’s disease and ulcerative colitis have been linked to the administration of combined oral contraceptives.
Particularly in women with a history of melasma gravidarum, melasma may occur occasionally. Where there is a tendency for melasma, sunlight and UV radiation are therefore to be avoided during the use of combined oral contraceptives.
[XXX] contains lactose. Users with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. All the above information must be considered when weighing up and selecting a suitable contraceptive method.
Medical investigation/consultation
Prior to the initiation or reinstitution of [XXX] 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). It is important to draw a woman’s attention to the information on venous and arterial thrombosis, including the risk of [XXX] compared with other CHCs, the symptoms of VTE and ATE, the known risk factors and what to do in the event of a suspected thrombosis.
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.
Women should be advised that hormonal contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.
Reduced efficacy The efficacy of combined oral contraceptives may be impaired, e.g. in the case of missed doses (section 4.2.), gastrointestinal complaints (section 4.2.) or coadministration of other medicinal products (section 4.5.).
Plant medicines containing St John’s wort (Hypericum perforatum) should not be administered concomitantly with [XXX] because there is a risk that plasma concentrations will be reduced and the efficacy of [XXX] impaired (see section 4.5 Interactions).
Impairment of cycle control Irregular bleeding (spotting or breakthrough bleeding) may occur with all combined oral contraceptives, particularly in the first months of administration. Diagnostic clarification of irregular bleeding is therefore appropriate only after an adjustment phase of about 3 cycles.
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If the bleeding irregularities persist or they arise after previously regular cycles, non-hormonally- related causes must also be considered. Appropriate diagnostic measures to rule out pregnancy or a malignant disease are accordingly indicated, where necessary including curettage.
Withdrawal bleeding may fail to occur during the administration-free interval. If the combined oral contraceptive has been taken in accordance with the instructions in section 4.2, pregnancy is unlikely. However, if combined oral contraceptives have not been taken according to the instructions before the first no-show withdrawal bleeding or if there are two successive withdrawal bleedings missing, pregnancy must be ruled out before the further administration of combined oral contraceptives.
4.5 Interaction with other medicinal products and other forms of interaction
Influence of other medical products on
Hepatic metabolism Interactions can occur with medicinal products that induce microsomal enzymes and may therefore accelerate the clearance of sex hormones, e.g. hydantoins, barbiturates, primidone, bosentane, carbamazepine, rifampicin, rifabutin and possibly also oxcarbazepine, modafinil, topiramate, felbamate, ritonavir, griseofulvin and products containing St John’s wort. Also HIV protease inhibitors with an inducing potential (e.g. ritonavir and nelfinavir) and non- nucleoside reverse transcriptase inhibitors (e.g. nevirapine and efavirenz), may affect hepatic metabolism. Although enzyme induction generally peaks only after 2 to 3 weeks, it persists for at least 4 weeks beyond withdrawal of the medicinal product therapy.
Management Women treated with one of these medicinal products should, in addition to the combined oral contraceptive, temporarily use a mechanical contraceptive or choose a different method of birth control. A mechanical contraceptive method should additionally be used for up to 28 days after and during a concomitant treatment with microsomal enzyme-inducing medicinal products. In the case of long-term therapy with microsomal enzyme-inducing medicinal products, a different method of birth control should be considered. If the concomitant use of a mechanical method of birth control must be continued beyond the end of the current blister pack of combined oral contraceptive, the next blister pack of the combined oral contraceptive is to be started without a break, i.e. without observing the usual administration-free interval.
Influence of
Note: The product information of the concomitant medicinal product should be consulted to determine possible interactions.
Laboratory tests When combined oral contraceptives are used, the results of certain laboratory tests may be influenced, including biochemical parameters for hepatic, thyroid, adrenal and renal function, and also plasma levels of (carrier) proteins, such as transcortin (CBG) and lipid or lipoprotein fractions, parameters of carbohydrate metabolism as well as blood clotting and fibrinolysis. These changes generally vary within the corresponding normal range.
4.6 Fertility, pregnancy and lactation
Pregnancy [XXX] is not indicated during pregnancy. If a pregnancy occurs during the use of [XXX], the preparation is to be withdrawn. In most epidemiological studies, however, there was neither an
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increased risk of malformations in children whose mothers had taken oral contraceptives before pregnancy nor a teratogenic effect from inadvertent administration of combined oral contraceptives in early pregnancy.
The increased risk of VTE during the postpartum period should be considered when re-starting [XXX] (see section 4.2 and 4.4).
Breast-feeding Lactation may be influenced by combined oral contraceptives because they may reduce the quantity of breast milk and change its composition. Until the nursing mother has fully weaned her child, administration of combined oral contraceptives should therefore generally not be recommended. Although small quantities of the contraceptively active steroids and/or their metabolites may end up in milk, there is no evidence of adverse effects on the child’s health.
4.7 Effects on ability to drive and use machines
Effects on ability to drive and use machines have not been reported.
4.8 Undesirable effects
As with all COCs, changes in vaginal bleeding patterns may occur, especially during the first months of use. These may include changes in bleeding frequency (absent, less, more frequent or continuous), intensity (reduced or increased) or duration.
Possibly related undesirable effects that have been reported in users of ethinylestradiol/desogestrel or COC users in general are listed in the table below.
Organ system Frequency of adverse reactions Common Uncommon Rare (> 1/100) (> 1/1,000, < 1/100) (< 1/1,000) Immune system Hypersensitivity disorders Metabolism and Fluid retention nutrition disorder Psychiatric disorders Depressive mood, mood Reduced libido Increased libido swings Nervous system Headache Migraine disorders Eye disorders Complaints associated with wearing contact lenses Vascular disorders Venous/arterial thromboembolism (VTE/ATE) Gastrointestinal Nausea, abdominal pain Vomiting, diarrhoea disorders Skin and subcutaneous Skin rash, urticaria Erythema nodosum, tissue disorders erythema multiforme Reproductive system Chest pain, sensation of Breast enlargement Vaginal discharge, and breast disorders tension in the chest mammary gland secretion
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Investigations Weight gain Weight loss
Description of selected adverse reactions An increased risk of arterial and venous thrombotic and thrombo-embolic events, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis and pulmonary embolism has been observed in women using CHCs, which are discussed in more detail in section 4.4. Other side-effects discussed in section 4.4. are hypertension, hormone-dependent tumours (e.g. liver tumours, breast cancer) and melasma.
Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via
[to be completed nationally]
4.9 Overdose
There are no reports of serious consequences from overdose. Symptoms of overdose are: nausea, vomiting and mild vaginal bleeding in young girls. There is no known antidote, therapy should be carried out symptomatically.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Progestogens and estrogens, fixed combinations ATC code: G03AA09
The contraceptive action of combined oral contraceptives is based on various factors, with the most important of these being inhibition of ovulation and modification of cervical secretion. Besides the contraceptive action, combined oral contraceptives have various favourable properties which, taking account of the negative effects (see Special warnings, Undesirable effects), may influence the choice of method of birth control. Cycles become more regular, menstruation often becomes less painful and bleeding is weaker. The latter reduces the frequency of iron deficiency. In addition, the following have manifested themselves, at least under higher-dose combined oral contraceptives (50 µg ethinylestradiol): a reduced risk of fibrocystic mastopathies, ovarian cysts, infections of internal genital organs (pelvic inflammatory disease), ectopic pregnancies and endometrial or ovarian carcinomas. To what extent this also applies to lower-dosed combined oral contraceptives is yet to be proven.
Paediatric population: No clinical data on efficacy and safety are available in adolescents below 18 years.
5.2 Pharmacokinetic properties
Desogestrel
Absorption After oral administration, desogestrel is absorbed rapidly and fully and converted to etonogestrel. Maximum blood levels are achieved around 1.5 hours after administration of a single dose. Bioavailability is 62 to 81%.
Distribution Etonogestrel is bound both to albumin and to sex hormone-binding globulin (SHBG). Only 2 to 4% of the total concentration in the serum are free steroid, 40 to 70% are specifically bound to SHBG. The
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ethinylestradiol-induced increase in the SHBG concentration influences the relative binding to serum proteins, which leads to an increase in SHBG binding and to a decrease in albumin binding. The (apparent) distribution volume of desogestrel is 1.5 l/kg.
Biotransformation Etonogestrel is completely metabolised via the known pathways of steroid breakdown. Metabolic clearance from the serum is 2 ml/min/kg. There are no metabolic interactions due to coadministration of ethinylestradiol.
Elimination Etonogestrel serum levels fall in a two-phase manner with a half-life of 30 hours in the terminal disposition phase. Desogestrel and its metabolites are excreted with the urine and bile in a ratio of approx. 6 : 4.
Steady-state conditions The pharmacokinetics of etonogestrel is influenced by SHBG levels, which are increased threefold by ethinylestradiol. With daily administration, serum levels rise by approx. two to three times, with the steady state being achieved in the second half of the administration cycle.
Ethinylestradiol
Absorption After oral administration, ethinylestradiol is absorbed rapidly and completely. Maximum blood levels are achieved after 1 to 2 hours. Absolute bioavailability as a result of presystemic conjugate formation and the first-pass effect is approx. 60%.
Distribution Ethinylestradiol is bound to a large extent, but non-specifically, to serum albumin (approx. 98.5%) and induces an increase in the serum concentration of SHBG. The (apparent) distribution volume is approx. 5 l/kg.
Biotransformation Ethinylestradiol is conjugated presystemically both in the mucosa of the small intestine and in the liver. It is metabolised primarily by aromatic hydroxylation and converted to a number of hydroxylated and methylated metabolites, which exist both in free form and as glucuronides and sulfates. Metabolic clearance is approx. 5 ml/min/kg.
Elimination The ethinylestradiol serum level falls in two disposition phases with a half-life of approx. 24 hours in the terminal disposition phase. Ethinylestradiol is not excreted in unchanged form. The metabolites are eliminated with the urine and bile in a ratio of 4:6 with a half-life of approx. 1 day.
Steady-state conditions Steady state is achieved after 3 to 4 days, with the serum concentration being 30 to 40% higher than after administration of a single dose.
5.3 Preclinical safety data
Preclinical data show no special risk for humans when combined oral contraceptives are used as recommended. This finding is based on conventional studies of chronic toxicity, genotoxicity, carcinogenic potential and reprotoxicity. It should nevertheless be borne in mind that sex steroids may promote the growth of certain hormone-dependent tissues and tumours.
6. PHARMACEUTICAL PARTICULARS
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6.1 List of excipients
Tablet Core: Lactose monohydrate Maize starch Maltodextrin Sodium starch glycolate (type A) Hypromellose Stearic acid Microcrystalline cellulose RRR-α-tocopherol
Coating: Hypromellose Lactose monohydrate Titanium dioxide (E171) Stearic acid Macrogol 4000 Microcrystalline cellulose Sodium citrate dihydrate.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
[PVC/aluminium blister (without sachet)] 3 years.
[PVC/aluminium blister, individually packed in sachets] 2 years.
6.4 Special precautions for storage
[PVC/aluminium blister (without sachet)] Do not store above 30°C.
[PVC/aluminium blister, individually packed in sachets] This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PVC/aluminium blister PVC/aluminium blister, individually packed in sachets.
Calendar packages with 1 x 21, 3 x 21 and 6 x 21 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special instructions for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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7. MARKETING AUTHORISATION HOLDER
<[to be completed nationally]>
8. MARKETING AUTHORISATION NUMBER(S)
<[to be completed nationally]>
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
<[to be completed nationally]>
10. DATE OF REVISION OF THE TEXT
<[to be completed nationally]>
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