DE/H/3115/001/IB/025 common-proposed-spc-en-cyproethinyl
SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
Cyproterone acetate and ethinylestradiol
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 1 film-coated tablet contains 2 mg cyproterone acetate and 0.035 mg ethinylestradiol.
Excipients with known effect: 1 film-coated tablet contains 47.4 mg Lactose monohydrate.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM Round, yellowish-buff coloured film-coated tablet
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of moderate to severe acne related to androgen-sensitivity (with or without seborrhoea) and/or hirsutism, in women of reproductive age. For the treatment of acne,
4.2 Posology and method of administration
Administration The tablets must be taken at about the same time each day, if required with some liquid, in the sequence indicated on the blister. One tablet must be taken daily for 21 consecutive days. Tablet-taking from the next pack is started after a 7-day tablet-free interval, during which time withdrawal bleeding usually occurs. This bleeding often starts 2-3 days after the last tablet and may still persist when tablet-taking from the next pack is started.
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Contraceptive protection starts on the first day of tablet-taking and is also afforded during the 7-day pauses. Concomitant use of hormonal contraceptives is therefore contraindicated.
Starting to take
Previous use of a combined oral contraceptive, vaginal ring or transdermal patch The user should preferably start taking
Switching from a progestogen-only product (minipill, injection, implant) or a progestogen-releasing intra-uterine system (IUS) If she has been taking the minipill, the user can start taking
Following a first-trimester abortion The user may start taking the tablets immediately. In this case, no additional contraceptive measures are required.
Following childbirth or a second-trimester abortion Tablet-taking should commence on days 21 to 28 postpartum or after a second-trimester abortion. If started any later, a barrier method must also be used during the first 7 days of tablet-taking. However, if sexual intercourse has already taken place, pregnancy must be excluded before starting the tablets or the user must wait until her first menstrual period.
Duration of use Time to relieve of symptoms is at least three months. The need to continue treatment should be evaluated periodically by the treating physician.
Management of missed tablets If the user has missed a
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Consequently, the following recommendations can be given in daily practice:
Week 1 The user should make up for the missed tablet as soon as possible, even if this means having to take two tablets at the same time. Subsequent tablets are then taken at the usual time. However, in the next 7 days, a barrier method, for example a condom, should additionally be used. If sexual intercourse has taken place in the previous 7 days, the possibility of pregnancy should be considered. The more tablets have been missed and the closer these are to the regular tablet-free interval, the greater the risk of pregnancy.
Week 2 The user should make up for the missed tablet as soon as possible, even if this means having to take two tablets at the same time. Subsequent tablets are then taken at the usual time. Provided that the tablets have been taken correctly on the 7 days previous to the first forgotten tablet, there is no need to use additional protective measures. If this was not the case or if more than 1 tablet has been missed, the use of additional protective measures over 7 days should be recommended.
Week 3 Full contraceptive protection can no longer be guaranteed on account of the imminent 7- day tablet-free interval. By adjusting the dosing schedule, however, a reduction in the contraceptive effect can still be prevented. If one of the following two procedures is followed, there is consequently no need for additional contraceptive measures, provided that the woman has taken her tablets correctly on the 7 days prior to the first missed tablet. If this is not the case, the woman should act as described in Point 1 and also use additional protective measures over the next 7 days.
1. The user should make up for the last missed tablet as soon as possible, even if this means having to take two tablets at the same time. She should then take the remaining tablets at the usual time. Tablet-taking from the next blister commences directly after finishing the current blister, i.e. there should be no tablet-free interval between the two packs. It is unlikely that the user will experience withdrawal bleeding before the end of the second pack; however, spotting or breakthrough bleeding may still occur whilst taking the tablets.
2. Discontinuation of the tablets from the current blister can also be recommended, which should then be followed by a tablet-free interval of up to 7 days, including the days when tablets were missed. Thereafter, the user should start taking tablets from the new blister. If any tablets have been missed and there is a subsequent absence of withdrawal bleeding in the next regular tablet-free interval, the possibility of pregnancy should be considered.
Absence of withdrawal bleeding In the absence of withdrawal bleeding,
Dealing with intermenstrual bleeding In the event of intermenstrual bleeding, the user must continue taking
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adjuvant administration of 25 – 50 µg ethinylestradiol daily (without exceeding the last tablet of any
Dealing with vomiting or severe diarrhoea Vomiting or severe diarrhoea may lead to incomplete absorption of the active substances. Other additional non-hormonal methods of contraception (excluding the Knaus-Ogino rhythm method and the temperature method) should be used. In the event of vomiting or severe diarrhoea within the first 3 to 4 hours after taking the tablet, the approach for missed tablets mentioned in section 4.2 “Posology and method of administration” should be applied. If the user concerned does not want to upset her normal dosing schedule, she must take the replacement tablet(s) from another blister.
Liver Upon resolution of viral hepatitis (normalisation of liver parameters), approximately six months should elapse before using preparations such as
4.3 Contraindications
Preparations with an oestrogen/progestogen combination may not be used if any of the following circumstances are present. If any of the disorders listed should occur for the first time whilst taking the combination product, the tablets must be discontinued immediately. - Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, -
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- Previous or existing severe hepatic dysfunction (including disorders of excretion such as Dubin-Johnson and Rotor syndrome) if liver function values have not yet normalised, - Previous or existing (benign or malignant) hepatic tumours, - Diagnostically unexplained vaginal bleeding, - History of migraine with focal neurological disorders, - Smokers (see section 4.4 "Special warnings and precautions for use"), - Known or suspected malignant disease of the genital organs or breasts, when these are influenced by sex hormones, - Idiopathic jaundice of pregnancy, severe pruritus in pregnancy or history of herpes gestationis, otosclerosis with deterioration during previous pregnancy, - Women currently wishing to conceive, pregnancy, lactation - meningioma or history of meningioma.
4.4 Special warnings and precautions for use
Duration of Use Time to relief of symptoms is at least three months. The need to continue treatment should be evaluated periodically by the treating physician (see section 4.2).
Medical examination/consultation Before use, a thorough general examination (including body weight, blood pressure, heart, legs and skin, urine glucose testing and, if appropriate, a specific liver diagnostic test) and gynaecological tests (including the breasts and cervical/vaginal cytology) should be performed and a careful family history taken, so that diseases requiring treatment and risk situations can be established. Pregnancy must be excluded. Check- ups at approximately half-yearly intervals are recommended during use. Disorders of the coagulation system must be excluded if thromboembolic disease (e.g. deep vein thrombosis, stroke, heart attack) has occurred in a blood relative at a relatively young age. Furthermore, it should be explained that taking oral contraceptives does not offer protection against HIV infections (AIDS) and other sexually transmitted diseases.
If any of the conditions/risk factors mentioned below is present, the benefits of the use of
Circulatory disorders The use of
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Epidemiological studies have shown that the incidence of VTE is 1.5 to 2 times higher in users of
The risk of arterial thromboembolic complications or of a cerebrovascular accident increases with: - increasing age; - smoking (with heavier smoking and increasing age the risk further increases, especially in women over 35 years of age. Women over 35 years of age should be strongly advised not to smoke if they wish to use
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syndrome, chronic inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis) and sickle cell disease. The increased risk of thromboembolism in the puerperium must be considered (for information on ‘Pregnancy and lactation’ see section 4.6). An increase in frequency or severity of migraine during use of
Women using
Tumors In some epidemiological studies, an increased risk of cervical carcinoma has been reported with long-term use of combined oral contraceptives. In this regard, there is still much debate regarding the role played by the effects of sexual behaviour, which are difficult to assess, and other factors such as infection with the human papillomavirus (HPV). A meta-analysis examining 54 epidemiological studies revealed a slightly increased relative risk (RR = 1.24) of breast cancer in women currently using combined oral contraceptives. The increased risk gradually recedes over the course of 10 years upon discontinuation of combined oral contraceptives. As breast cancer rarely occurs in women under 40 years of age, the number of additionally diagnosed breast cancer cases in users currently or recently taking a combined oral contraceptive is low in relation to the overall risk of developing breast cancer. These studies yield no evidence of causality. The increased risk profile observed can be attributed to earlier diagnosis of breast cancer in users of combined oral contraceptives, the biological effects of this medicinal product or a combination of both. In women who have always taken combined oral contraceptives, diagnosed breast cancer tends to be at a less advanced clinical stage than breast cancer diagnosed in women who have never used combined oral contraceptives. In rare cases following use of steroid hormones, including the active substances contained in
Malignancies may be life-threatening or may have a fatal outcome.
Meningioma The occurrence of meningiomas (single and multiple) has been reported in association with use of cyproterone acetate, especially at high doses of 25 mg and above and for prolonged time (see section 5.1). If a patient is diagnosed with meningioma, any cyproterone containing treatment, including Cyproderm, must be stopped, as a precautionary measure.
Grounds for immediate discontinuation of
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- first signs of thrombophlebitis or thromboembolic phenomena (e.g. unusual pain or swelling in one or both legs, stabbing pain on breathing or cough of unclear cause). Chest pain or tight-chestedness, - 4 weeks prior to scheduled major surgery (e.g. abdominal, orthopaedic), any surgery on the legs, medical treatment of varicose veins or prolonged immobilisation, e.g. after accidents or surgery. Tablet-taking must not be resumed for at least two weeks after complete mobilisation. In the event of emergency surgery, thrombosis prophylaxis is usually indicated, e.g. with subcutaneous heparin. - onset of jaundice, hepatitis or generalised pruritus, - increase in epileptic attacks, - moderate rise in blood pressure, - onset of severe depression, - severe epigastric pain or hepatomegaly, - significant deterioration of disorders known to worsen during the use of hormonal contraceptives or pregnancy, - Pregnancy constitutes grounds for immediate discontinuation, as some studies suggest that oral contraceptives taken in early pregnancy might slightly increase the risk of foetal malformations. Conversely, other studies do not confirm this. However, the possibility cannot be completely excluded. If such a risk should exist at all, it is sure to be small.
Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use (see section 4.8). Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their physician in case of mood changes and depressive symptoms, including shortly after initiating the treatment.
Disorders/risk factors requiring particular medical surveillance: Benign uterine growths, multiple sclerosis, tetany, renal dysfunction, family history of breast cancer and patient history of benign breast disease, an intolerance to contact lenses, asthma.
Furthermore, women over 40 years of age and women with a history of phlebitis or diabetic tendency should receive particular monitoring. It should be remembered that there is an increased risk for the occurrence of thromboembolic events in the puerperium (for information on pregnancy and lactation, see section 4.6). Other disorders in which vascular complications may occur are polycystic ovarian syndrome, haemolytic-uraemic syndrome and chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis).
Women with hypertriglyceridaemia or a positive family history thereof may be at increased risk of developing pancreatitis whilst taking combined oral contraceptives.
Although a slight increase in blood pressure has been reported in many women taking combined oral contraceptives or
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The following disorders are reported to occur or worsen both during pregnancy and use of a combined oral contraceptive; no definite connection with the use of combined oral contraceptives has yet been established: cholestatic jaundice and/or pruritus; cholelithiasis; porphyria; systemic lupus erythematosus; haemolytic-uraemic syndrome; Sydenham’s chorea; herpes gestationis; otosclerosis-related middle-ear hearing impairment, epilepsy. In women with hereditary angioedema, exogenously administered oestrogens can induce or exacerbate symptoms of angioedema. Acute or chronic hepatic dysfunction necessitates discontinuation of the combined oral contraceptive until liver function markers return within the normal range. In addition, recurrence of cholestatic jaundice and/or cholestatic pruritus that occurred in an earlier pregnancy or during previous use of steroid sex hormones requires the discontinuation of combined oral contraceptives. Although combined oral contraceptives may have an effect on peripheral insulin resistance and glucose tolerance, there is no indication of any need to modify the dosage in diabetics using combined oral contraceptives. However, diabetics must be carefully monitored, especially during initial use of such a product.
In addition, endogenous depression, epilepsy, Crohn’s disease and ulcerative colitis have been reported to deteriorate during use of combined oral contraceptives.
Chloasma can occasionally occur, particularly in women with a history of chloasma gravidarum. Women with this predisposition should therefore not directly expose themselves to the sun or ultraviolet light whilst taking combined oral contraceptives. If there has been a recent, significant deterioration in the symptoms of women suffering from hirsutism, the relevant causes (androgen-producing tumour, adrenocortical enzyme disturbances) must be clarified via a differential diagnosis.
Reduced efficacy The efficacy of
Reduced cycle control With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. 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.
If
Some women may experience amenorrhoea or oligomenorrhoea after discontinuation of
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Women should be advised that preparations like
ALT elevations During clinical trials with patients treated for hepatitis C virus infections (HCV) with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, transaminase (ALT) elevations higher than 5 times the upper limit of normal (ULN) occurred significantly more frequent in women using ethinylestradiol- containing medications such as combined hormonal contraceptives (CHCs). Additionally, also in patients treated with glecaprevir/pibrentasvir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs (see sections 4.3 and 4.5).
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take
4.5 Interaction with other medicinal products and other forms of interaction
Effect of other medicinal products on
Enzyme induction can already be observed after a few days of treatment. Maximal enzyme induction is generally seen within a few weeks. After the cessation of drug therapy, enzyme induction may be sustained for about 4 weeks.
Women treated with any of these medicinal products should use a barrier method in addition to
Substances that increase the clearance of
Substances with variable effects on the clearance of
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Substances decreasing the clearance of CHC (enzyme inhibitors) The clinical relevance of potential interactions with enzyme inhibitors remains unknown.
Concomitant administration of strong CYP3A4 inhibitors can increase plasma concentrations of the estrogen or the progestin or both.
Etoricoxib doses of 60 to 120 mg/day have been shown to increase plasma concentrations of ethinylestradiol 1.4 to 1.6- fold, respectively when taken concomitantly with a combined hormonal contraceptive containing 0.035 mg ethinylestradiol.
Effect of oestrogen/progestogen combinations on other medicinal products Oestrogen/progestogen combinations such as
Clinical data suggest that ethinylestradiol is inhibiting the clearance of CYP1A2 substrates leading to a weak (e.g. theophylline) or moderate (e.g. tizanidine) increase in their plasma concentration.
Other 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.
Note
Pharmacodynamic interactions Concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin or glecaprevir/pibrentasvir may increase the risk of ALT elevations (see sections 4.3 and 4.4). Therefore,
4.6 Fertility, pregnancy and lactation
Pregnancy
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Breast-feeding
Fertility
4.7 Effects on ability to drive and use machines
No effects on the ability to drive and use machines have been observed.
4.8 Undesirable effects
The most commonly reported adverse reactions with
There is an increased risk of thromboembolism for all women who use
In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.
For other serious undesirable effects, such as liver tumours, cervical cancer and breast cancer, see section 4.4 “Special warnings and precautions for use”. Other undesirable effects reported by users of COCs are:
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SYSTEM Frequency of undesirable effects ORGAN CLASS Common Uncommon Rare Not known (≥ 1/100 to (≥1/1,000 to (≥1/10,000 to (cannot be <1/10) <1/100) <1/1,000) estimated from the available data) Eye disorders Contact lens intolerance Vascular Thromboembolis Increased blood disorders m pressure Gastrointestinal Nausea, Vomiting, disorders abdominal pain diarrhoea Immune system Hypersensitivity disorders reactions Investigations Weight gain Blood pressure Weight loss elevations Metabolism and Fluid retention nutrition disorders Nervous system Headache Migraine disorders
Psychiatric Depressive libido decreased libido increased disorders moods, mood lability Reproductive Breast pain, Breast Mammary gland system and breast hypertrophy secretion, breast disorders tenderness, change in intermenstrual vaginal bleeding secretion, Skin and Rash, urticaria, Erythema subcutaneous chloasma nodosum, tissue disorders erythema multiforme
In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema. An increased risk of arterial and venous thrombotic and thromboembolic 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.
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The following serious adverse events have been reported in women using CHCs, which are discussed in section 4.4 Special warnings and precautions for use: - Venous thromboembolic disorders; - Arterial thromboembolic disorders; - Hypertension; - Liver tumors; - Occurrence or deterioration of conditions for which association with COC use is not conclusive: Crohn’s disease, ulcerative colitis, epilepsy, uterine myoma, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham's chorea, haemolytic uremic syndrome, cholestatic jaundice; - Chloasma; - Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. - In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.
The frequency of diagnosis of breast cancer is very slightly increased among COC users. As breast cancer is rare in women under 40 years of age the excess number is small in relation to the overall risk of breast cancer. Causation with COC use is unknown. For further information, see sections 4.3 and 4.4.
If in women suffering from hirsutism, symptoms have recently developed or increased substantially, the causes (androgen-producing tumor, adrenal enzyme defect) must be clarified by differential diagnosis.
Interactions Breakthrough bleeding and/or contraceptive failure may result from interactions of other drugs (enzyme inducers) with oral contraceptives (see section 4.5).
Effect on normal clinical/chemical values There may be rise in the erythrocyte sedimentation rate without the presence of disease. A rise in serum copper and serum iron levels has also been reported, as well as a rise in alkaline leukocyte phosphatase.
Other metabolic functions In isolated cases, disturbances of folic acid and tryptophan metabolism may occur.
Due to its composition,
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 the national reporting system listed in Appendix V.
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4.9 Overdose
There is no experience with overdose in humans. Based on the general experience gathered with combined oral contraceptives, the following symptoms may possibly occur in such cases: nausea, vomiting, unexpected vaginal bleeding. Withdrawal bleeding may even occur in girls before their menarche, if they accidental take the medicinal product. There is no antidote; if needed, treatment should be symptomatic.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antiandrogens and oestrogens, cyproterone and oestrogen ATC code: G03HB01
The sebaceous gland is androgen-sensitive. Among other factors, acne and seborrhoea are due to impaired sebaceous gland function, caused by increased peripheral sensitivity or increased androgen levels in plasma. Both active substances in
Cyproterone acetate is also a potent progestogen which has a contraceptive effect in combined use with ethinylestradiol. This effect is based on interaction of central and peripheral mechanisms, the most important of which can be regarded as ovulation inhibition and changes in cervical secretion. Furthermore, as a result of the morphological and enzymatic changes, the endometrium offers extremely unfavourable conditions for nidation. Contraceptive protection starts from the first day of tablet-taking.
Meningioma Based on results from a French epidemiological cohort study, a cumulative dose- dependent association between cyproterone acetate and meningioma has been observed. This study was based on data from the French Health Insurance (CNAM) and included a population of 253,777 women using 50 - 100 mg cyproterone tablets. The incidence of meningioma treated with surgery or radiotherapy was compared between women exposed to high-dose cyproterone acetate (cumulative dose ≥3 g) and women who were slightly exposed to cyproterone acetate (cumulative dose <3 g). A cumulative dose-response relationship was demonstrated.
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a Cumulative dose of Incidence rate (in patient- HRadj (95% CI) cyproterone acetate years) Slightly exposed (<3 g) 4.5/100,000 Ref. Exposed to ≥3 g 23.8/100,000 6.6 [4.0-11.1] 12 to 36 g 26/100,000 6.4 [3.6-11.5] 36 to 60g 54.4/100,000 11.3 [5.8-22.2] more than 60 g 129.1/100,000 21.7 [10.8-43.5] a Adjusted based on age as a time-dependent variable and oestrogen at inclusion A cumulative dose of 12g for example can correspond with one year of treatment with 50 mg/day for 20 days each month.
5.2 Pharmacokinetic properties
Cyproterone acetate (CPA) Absorption Following oral administration, CPA is completely absorbed over a wide dose range. Ingestion of
Distribution In serum, CPA is available almost exclusively in protein-bound form. About 3.5 – 4.0% of CPA is available in free form; the remainder is bound to albumin. Binding of CPA to sex hormone-binding globulin (SHBG) cannot be demonstrated; thus, changes in the SHBG concentration caused by ethinylestradiol also exert no effect on the pharmacokinetics of CPA.
Metabolism CPA is metabolised via various degradation pathways, including via hydroxylation and conjugation stages. The main metabolite in human plasma is 15-hydroxy-CPA.
Excretion Serum concentrations decline in two phases with half-lives of 0.8 hours and 2.3 days. Clearance of CPA from serum is 3.6 ml·min-1·kg-1. A fraction of the administered CPA dose is excreted unchanged via the bile. The major fraction of the dose is excreted in the form of metabolites via the kidneys and bile at a ratio of 3:7 with a half-life of 1.9 days. Elimination of metabolites from plasma takes place at a similar rate (half-life of 1.7 days).
Steady-state conditions Due to the long terminal elimination half-life of CPA from serum, CPA can be expected to accumulate in serum at daily dosing within one cycle. Mean peak serum levels increase from 15 ng/ml (day 1) to 21 ng/ml and 24 ng/ml by the end of the first and third treatment cycle, respectively. Steady-state conditions are reached after about 10 days.
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During long-term treatment, CPA accumulates during the course of treatment cycles by a factor of about 2 – 2.5. Smoking had no influence on the pharmacokinetics of CPA.
Ethinylestradiol (EE2) Absorption Orally administered EE2 is rapidly and completely absorbed. Following single ingestion of
Distribution For EE2, an apparent volume of distribution of about 5 l/kg has been established. EE2 is extensively but not specifically bound to serum albumin. 2% of the substance is available in free form. The bioavailability of EE2 can be altered by other medicinal substances in both directions. However, there is no interaction with high-dose vitamin C. At repeated dosing, EE2 induces the hepatic synthesis of SHBG and corticosteroid-binding globulin (CBG). However, the extent of SHBG induction is dependent on the chemical structure and the dose of the co-administered progestogen. During treatment with preparations comparable to
Metabolism During absorption and first passage through the liver, EE2 is metabolised, resulting in a reduced absolute and variable oral bioavailability. For EE2, metabolic clearance from plasma has been determined to be about 5 ml/min/kg.
In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1 and CYP1A2 as well as a mechanism based inhibitor of CYP3A4/5, CYP2C8 and CYP2J2.
Excretion EE2 concentrations in plasma decline in two phases, with half-lives of 1 – 2 hours and about 20 hours. For analytical reasons, these parameters can only be calculated after administration of higher doses. Unchanged EE2 is not excreted. The metabolites of EE2 are excreted via the kidneys and bile at a ratio of 4:6, with a half-life of about 1 day.
Steady-state conditions Consistent with the terminal disposition half-life of EE2 from serum and daily dosing, a 30 – 40% rise in EE2 concentration is observed compared with single administration, reaching a plateau after 3 – 4 days.
5.3 Preclinical safety data
Ethinylestradiol The toxicity profile of ethinylestradiol is well known. In laboratory animals, the effects of ethinylestradiol was confined to those associated with the recognised pharmacological action. Preclinical data reveal no relevant risks for humans other than those already described in other sections of this Summary of Product Characteristics.
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Cyproterone acetate Systemic toxicity Studies of repeated dose toxicity revealed no evidence of specific risks when using
Toxicity to reproduction, teratogenicity Administration of cyproterone acetate during the hormone-sensitive differentiation phase of the genital organs causes signs of feminisation in male foetuses after high doses. Observation of male neonates exposed in utero to cyproterone acetate revealed no signs of feminisation. Nevertheless, pregnancy represents a contraindication for the use of
Genotoxicity, carcinogenicity Testing of cyproterone acetate in a recognised standard test battery yielded no evidence of a mutagenic effect. However, in further studies, cyproterone acetate led to DNA adduct formation (and an increase in repair synthesis) in hepatic cells of rats, monkeys and humans.
This DNA adduct formation was observed under conditions of exposure that might occur at the recommended therapeutic dosage. A consequence of the in vivo treatment was an increased incidence of focal, possibly preneoplastic liver cell foci with altered enzyme expression in female rats.
The clinical significance of this finding is currently uncertain. Clinical experience to date does not indicate any increased incidence of liver tumours in humans.
Tumorigenicity studies on rodents mainly revealed no abnormal findings compared with other steroid hormones. Nevertheless, it must be considered that sex steroids can promote the growth of certain hormone-dependent tissues and tumours. Overall, these results raise no concerns for the use of
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core: Lactose monohydrate Maize starch Maltodextrin Magnesium stearate
Tablet coating: Hypromellose Macrogol 400 Macrogol 4000
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Lactose monohydrate Sodium citrate dihydrate Titanium dioxide (E 171) Iron oxide yellow (E 172) Iron oxide red (E 172) Iron oxide black (E 172) Quinoline yellow aluminium lake (E 104)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
48 months
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PVC/PE/PVDC/aluminium foil blisters containing 21 film-coated tablets 2 x 21 film-coated tablets 3 x 21 film-coated tablets and 6 x 21 film-coated tablets.
Not all pack sizes will be marketed.
6.6 Special precautions for disposal
No special requirements.
7. MARKETING AUTHORISATION HOLDER
8. MARKETING AUTHORISATION NUMBER
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10. DATE OF REVISION OF THE TEXT
{month YYYY}
DE/H/3115 - safety variation Page 19 of 19
2021-04-28 Page 19 of 19