Summary of medicine characteristics - CYPROTERONE ACETATE 2.0 MG ETHINYLESTRADIOL 0.035 MG TABLETS
Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg Coated Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
2 QUALITATIVE AND QUANTITATIVE COMPOSITIONEach coated tablet contains 2mg of cyproterone acetate and 0.035mg of ethinylestradiol.
Excipient(s) with known effect
Each coated tablet contains 27.659 mg of lactose (as monohydrate) and 19.637 mg of sucrose
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
3 PHARMACEUTICAL FORMCoated tablet.
Yellow , biconvex, round sugar-coated tablet with a 5. 6 – 5.8 mm nominal diameter.
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, Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg should only be used after topical therapy or systemic antibiotic treatments have failed.
Since Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg is also a hormonal contraceptive, it should not be used in combination with other hormonal contraceptives (see section 4.3).
4.2 Posology and method of administration
Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg inhibits ovulation and thereby prevents conception. Patients who are using Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg should not therefore use an additional hormonal contraceptive, as this will expose the patient to an excessive dose of hormones and it is not necessary for effective contraception.
Posology
First treatment course:
One tablet daily for 21 days, starting on the first day of the menstrual cycle (the first day of menstruation counting as Day 1).
Women with amenorrhoea should start therapy immediately. In this case the first day of tablet intake is considered as the first day of the cycle.
Subsequent courses:
Each subsequent course is started after 7 tablet-free days have followed the preceding course.
When the contraceptive action of Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg is also to be employed, it is essential that the above instructions be rigidly adhered to. Should bleeding fail to occur during the tablet-free interval, the possibility of pregnancy must be excluded before the next pack is started.
When changing from an oral contraceptive and relying on the contraceptive action of Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035mg Coated Tablets, follow the instructions given below:
Changing from 21-day combined oral contraceptives: The first tablet of Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg should be taken on the first day immediately after the end of the previous oral contraceptive course. Additional contraceptive precautions are not required.
Changing from a combined Every Day pill (28 day tablets):
Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg should be started after taking the last active tablet from the Every Day Pill pack. The first Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg tablet is taken the next day. Additional contraceptive precautions are not then required.
Changing from a progestogen-only pill (POP):
The first tablet of Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg should be taken on the first day of bleeding, even if a POP has already been taken on that day. Additional contraceptive precautions are not then required. The remaining progestogen-only pills should be discarded.
Post-partum and post-abortum use:
After pregnancy, Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg can be started 21 days after a vaginal delivery, provided that the patient is fully ambulant and there are no puerperal complications. Additional contraceptive precautions will be required for the first 7 days of pill taking. Since the first post-partum ovulation may precede the first bleeding, another method of contraception should be used in the interval between childbirth and the first course of tablets. Lactation is contra-indicated with Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg. After a first-trimester abortion, Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg may be started immediately in which case no additional contraceptive precautions are required. 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.
The length of use depends on the severity of the clinical picture. Complete remission of acne is expected within a few months of commencing treatment, but in particularly severe cases treatment for longer may be necessary before the full benefit is seen. It is recommended that treatment be withdrawn 3 to 4 cycles after the acne has satisfactorily resolved and that Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg is not continued solely to provide oral contraception. Repeat courses of Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg may be given if the androgen-dependent acne recurs. In this case, an early restart of Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg should be considered. In case of a restart of Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg (following a 4 week or greater pill free interval), the increased risk of VTE should be considered (see section 4.4).
Special circumstances requiring additional contraception
Incorrect administration:
A single delayed tablet should be taken as soon as possible, and if this is within 12 hours of the correct time, contraceptive protection is maintained. With longer delays, additional contraception is needed. Only the most recently delayed tablet should be taken, earlier missed tablets being omitted. Additional non-hormonal methods of contraception (except the rhythm or temperature methods) should be used for the next 7 days, while the next 7 tablets are being taken. Additionally, therefore, if tablet(s) have been missed during the last 7 days of a pack, there should be no break before the next pack is started. In this situation, a withdrawal bleed should not be expected until the end of the second pack. Some breakthrough bleeding may occur on tablet taking days but this is not clinically significant. If the patient does not have a withdrawal bleed during the tablet-free interval following the end of the second pack, the possibility of pregnancy must be ruled out before starting the next pack. Gastrointestinal upset:
Vomiting or diarrhoea may reduce the efficacy of oral contraceptives by preventing full absorption. Tablet-taking from the current pack should be continued Additional non-hormonal methods of contraception (except the rhythm or temperature methods) should be used during the gastrointestinal upset, and for 7 days following the upset. If these 7 days overrun the end of a pack, the next pack should be started without a break. In this situation, a withdrawal bleed should not be expected until the end of the second pack. If the patient does not have a withdrawal bleed during the tablet-free interval following the end of the second pack the possibility of pregnancy must be ruled out before starting the next pack. Other methods of contraception should be considered if the gastrointestinal disorder is likely to be prolonged.
Additional information on special populations
Children and adolescents
Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg is only indicated after menarche.
Elderly
Not applicable. Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg is not indicated after menopause.
Hepatic impairment
Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg is contraindicated in women with severe hepatic diseases as long as liver function values have not returned to normal. See also section 4.3.
Renal impairment
Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg has not been specifically studied in renally impaired patients. Available data do not suggest a change in treatment in this patient population.
Method of administration
Oral use.
4.3 Contraindications
Preparations containing oestrogen/progestogen combinations should not be used in the presence of any of the conditions listed below. Should any of the conditions appear for the first time during their use, the product should be stopped immediately.
Concomitant use with another hormonal contraceptive (see section 4.1)
Venous thrombosis present or in history (deep venous thrombosis, pulmonary embolism)
Arterial thrombosis present or in history (e.g. myocardial infarction) or prodromal conditions (e.g. angina pectoris and transient ischaemic attack)
Presence or history of cerebrovascular accident
The presence of a severe or multiple risk factor(s) for venous or arterial thrombosis (see section 4.4) such as:
– diabetes mellitus with vascular symptoms
– severe hypertension
– severe dyslipoproteinaemia
Hereditary or acquired predisposition for venous or arterial thrombosis, such as activated protein C (APC) resistance, antithrombin-III-deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant)
Known or suspected pregnancy (see section 4.6)
Breast-feeding (see section 4.6)
Presence or history of severe hepatic disease e.g. active viral hepatitis and severe cirrhosis, as long as liver function values have not returned to normal
Presence or history of liver tumours (benign or malignant)
Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg is contraindicated for concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, or medicinal products containing glecaprevir/pibrentasvir (see sections 4.4 and section 4.5)
Known or suspected sex-steroid influenced malignancies (e.g. of the genital organs or the breasts)
Undiagnosed abnormal vaginal bleeding
History of migraine with focal neurological symptoms
Meningioma or history of meningioma
Hypersensitivity to cyproterone acetate, ethinylestradiol or to any of the excipients listed in section 6.1.
Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg is not for use in men.
4.4 Special warnings and precautions for use
Medical Examination
Assessment of women prior to starting oral contraceptives (and at regular intervals thereafter) should include a personal and family medical history of each woman. Physical examination should be guided by this and by the contraindications (section 4.3) and warnings (section 4.4) for this product. The frequency and nature of these assessments should be based upon relevant guidelines and should be adapted to the individual woman, but should include measurement of blood pressure and, if judged appropriate by the clinician, breast, abdominal and pelvic examination including cervical cytology.
Exclude the likelihood of pregnancy before starting treatment.
Undiagnosed vaginal bleeding that is suspicious for underlying conditions should be investigated.
Warnings
Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg is composed of the progestogen cyproterone acetate and the oestrogen ethinylestradiol and is administered for 21 days of a monthly cycle. It therefore has a similar composition to that of a combined oral contraceptive (COC).
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).
Women should be advised that Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 does not protect against HIV infections (AIDS) and other sexually transmitted diseases.
Conditions which require strict medical supervision
If any of the conditions/risk factors mentioned below is present, the benefits of the use of Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start using Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the woman should contact her physician. The physician should then decide on whether the use of Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 should be discontinued.
Diabetes mellitus, with mild vascular disease or mild nephropathy, retinopathy or neuropathy
Hypertension that is adequately controlled, i.e. systolic >140 to159 mm Hg or
diastolic > 90 to 94mmHg (see also Section 4.4 ‚Reasons for stopping Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 immediately‘)
Porphyria
Clinical depression
Obesity
Migraine
Cardiovascular diseases
Chloasma
Patients with a history of depression or any condition mentioned above should be monitored during treatment with Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035.
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.
When stopping oral contraception non-hormonal contraception should be used to ensure contraceptive protection is maintained, if needed.
1. Occurrence for the first time, or exacerbation, of migrainous headaches or unusually frequent or unusually severe headaches.
2. Sudden disturbances of vision or hearing or other perceptual disorders.
3. First signs of thrombosis or blood clots (e.g. unusual pains in or swelling of the leg(s), stabbing pains on breathing or coughing for no apparent reason). Feeling of pain and tightness in the chest.
4. Six weeks before an elective major operation (e.g. abdominal, orthopaedic), any surgery to the legs, medical treatment for varicose veins or prolonged immobilisation, e.g. after accidents or surgery. Do not restart until 2 weeks after full ambulation. In case of emergency surgery, thrombotic prophylaxis is usually indicated e.g. subcutaneous heparin.
5. Onset of jaundice, hepatitis, itching of the whole body.
6. Significant rise in blood pressure
7. Onset of severe depression.
8. Severe upper abdominal pain or liver enlargement.
9. Clear worsening of conditions known to deteriorate during use of hormonal contraception or during pregnancy (see section 4.4).
10. Pregnancy is a reason for stopping immediately (see section 4.6)
11. 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 Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg must be stopped, as a precautionary measure.
Circulatory disorders
The use of cyproterone acetate/ethinylestradiol carries an increased risk of venous thromboembolism (VTE) compared with no use. The excess risk of VTE is highest during the first year a woman starts cyproterone acetate/ethinylestradiol or when restarting or switching after a pill-free interval of at least a month. Venous thromboembolism can be fatal in 1–2% of cases.
Epidemiological studies have shown that the incidence of VTE is 1.5 to 2 times higher in users of cyproterone acetate/ethinylestradiol than in users of levonorgestrel-containing combined oral contraceptives (COCs) and may be similar to the risk for desogestrel / gestodene / drospirenone-containing COCs.
The user group of cyproterone acetate/ethinylestradiol is likely to include patients that may have an inherently increased cardiovascular risk such as that associated with polycystic ovarian syndrome.
Epidemiological studies have also associated the use of hormonal contraceptive with an increased risk for arterial (myocardial infarction, transient ischaemic attack) thromboembolism.
Extremely rarely, thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral or retinal veins and arteries, in hormonal contraceptive users.
Symptoms of venous or arterial thrombosis or of a cerebrovascular accident can include: unusual unilateral leg pain and / or swelling; sudden severe pain in the chest, whether or not it radiates to the left arm; sudden breathlessness; sudden onset of coughing; any unusual, severe, prolonged headache; sudden partial or complete loss of vision; diplopia; slurred speech or aphasia; vertigo; collapse with or without focal seizure; weakness or very marked numbness suddenly affecting one side or one part of the body; motor disturbances; ‘acute’ abdomen.
The risk of venous thromboembolic events 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 Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg
a positive family history (i.e. venous thromboembolism ever in a sibling or parent at a relatively early age). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any hormonal contraceptive use
prolonged immobilisation, major surgery, any surgery to the legs, or major trauma. In these situations it is advisable to discontinue use (in the case of elective surgery at least four weeks in advance) and not to resume until two weeks after complete remobilisation. Antithrombotic treatment should be considered if the use of Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg has not been discontinued in advance.
obesity (body mass index over 30 kg/m2)
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 Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg)
dyslipoproteinemia
obesity (body mass index over 30 kg/m2)
hypertension
migraine
valvular heart disease
atrial fibrillation
a positive family history (arterial thrombosis ever in a sibling or parent at a relatively early age). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any hormonal contraceptive use.
Other medical conditions, which have been associated with adverse circulatory events, include diabetes mellitus, systemic lupus erythematosus, haemolytic uraemic 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 Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg.
Women using Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg should be specifically pointed out to contact their physician in case of possible symptoms of thrombosis. In case of suspected or confirmed thrombosis, Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg use should be discontinued. Adequate contraception should be initiated because of the teratogenicity of anti-coagulant therapy (coumarins).
Arterial thromboembolic events may be life-threatening or may have a fatal outcome. The potential for an increased synergistic risk of thrombosis should be considered in women who possess a combination of risk factors or exhibit a greater severity of an individual risk factor. This increased risk may be greater than a simple cumulative risk of the factors. Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg should not be prescribed in case of a negative risk benefit assessment (see section 4.3).
Tumours
Like many other steroids, cyproterone acetate/ethinylestradiol, when given in very high doses and for the majority of the animal's life-span, has been found to cause an increase in the incidence of tumours, including carcinoma, in the liver of rats. The relevance of this finding to humans is unknown.
Numerous epidemiological studies have been reported on the risks of ovarian, endometrial, cervical and breast cancer in women using combined oral contraceptives. The evidence is clear that high dose combined oral contraceptives offer substantial protection against both ovarian and endometrial cancer. However, it is not clear whether low dose COCs or cyproterone acetate/confer protective effects to the same level.
Breast cancer
A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using combined oral contraceptives (COCs). The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both. The additional breast cancers diagnosed in current users of COCs or in women who have used COCs in the last ten years are more likely to be localised to the breast than those in women who never used COCs.
Breast cancer is rare among women under 40 years of age whether or not they take COCs. Whilst this background risk increases with age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer.
The most important risk factor for breast cancer in COC users is the age women discontinue the COC; the older the age at stopping, the more breast cancers are diagnosed. Duration of use is less important and the excess risk gradually disappears during the course of the 10 years after stopping COC use such that by 10 years there appears to be no excess.
The possible increase in risk of breast cancer should be discussed with the user and weighed against the benefits of COCs taking into account the evidence that they offer substantial protection against the risk of developing certain other cancers (e.g. ovarian and endometrial cancer).
Cervical Cancer
The most important risk factor for cervical cancer is persistent HPV infection. Some epidemiological studies have indicated that long-term use of COCs may further contribute to this increased risk but there continues to be controversy about the extent to which this finding is attributable to confounding effects, e.g., cervical screening and sexual behaviour including use of barrier contraceptives.
Liver Cancer
In rare cases benign and in even rarer cases malignant liver tumours leading in isolated cases to life-threatening intra-abdominal haemorrhage have been observed after the use of hormonal substances such as those contained in Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, a liver tumour should be included in the differential diagnosis.
Malignancies may be life-threatening or may have a fatal outcome.
Other conditions
The possibility cannot be ruled out that certain chronic diseases may occasionally deteriorate during the use of Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg (see Precautions).
Known hyperlipidaemias
Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs or Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg.
Women with hyperlipidaemias are at an increased risk of arterial disease (see section 4.4). However routine screening of women on COCs or Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg is not appropriate.
Blood pressure
Hypertension is a risk factor for stroke and myocardial infarction (see section 4.4 ‚Arterial thromboembolic-related conditions‘). Although small increases in blood pressure have been reported in many women taking COCs or
Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg, clinically relevant increases are rare. However, if sustained clinically significant hypertension develops during the use of a COC then it is prudent for the physician to withdraw the COC and treat the hypertension. Where considered appropriate, COC use may be resumed if normotensive values can be achieved with antihypertensive therapy.
Conditions which deteriorate with pregnancy or during previous COC or Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg use:
The following conditions have been reported to occur or deteriorate with both pregnancy and use of a COC or oestrogen/progestogen combinations like Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg, but the evidence of an association with COC use is inconclusive:
jaundice and/or pruritus related to cholestasis
gallstone formation
porphyria
systemic lupus erythematosus
hemolytic uremic syndrome
Sydenham's chorea
herpes gestationis
otosclerosis-related hearing loss
epilepsy
Crohn's disease and ulcerative colitis have been associated with the use of estrogen-progestin combinations.
In women with hereditary angioedema, exogenous oestrogens may induce or exacerbate symptoms of angioedema.
Disturbances of liver function
Acute or chronic disturbances of liver function may necessitate the discontinuation of COC or Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg use until markers of liver function return to normal.
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).
Diabetes (without vascular involvement)
Insulin-dependent diabetics without vascular disease can use Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg. However it should be remembered that all diabetics are at an increased risk of arterial disease and this should be considered when prescribing COCs or Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg. Diabetics with existing vascular disease are contraindicated from using Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg (see section 4.3).
Although COCs or oestrogen/progestogen combinations like Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics using low-dose COCs (containing < 0.05 mg ethinylestradiol). However, diabetic women should be carefully observed while taking COCs or Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg.
Chloasma
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg.
If in women suffering from hirsutism, symptoms have recently developed or increased substantially, the causes (androgen-producing tumour, adrenal enzyme defect) must be clarified by differential diagnosis.
Menstrual Changes
Reduction of menstrual flow: This is not abnormal and it is to be expected in some patients. Indeed, it may be beneficial where heavy periods were previously experienced.
Missed menstruation: Occasionally, withdrawal bleeding may not occur at all. If the tablets have been taken correctly, pregnancy is unlikely. Should bleeding fail to occur during the tablet-free interval the possibility of pregnancy must be excluded before the next pack is started.
Intermenstrual bleeding: 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. This may include curettage.
Some women may experience amenorrhoea or oligomenorrhoea after discontinuation of Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg, especially when these conditions existed prior to use. Women should be informed of this possibility.
Reduced efficacy
The contraceptive effect of Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg may be reduced in the event of e.g. missed tablets (see section 4.2), gastro-intestinal disturbances (see section 4.2) during tablet taking or concomitant medication (see section 4.5).
Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg contains lactose and sucrose
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption, should not take this medicinal product.
Patients with rare hereditary problems of fructose intolerance, glucosegalactose malabsorption or sucrase-isomaltase insufficiency should not take this medicinal product.
4.5 Interaction with other medicinal products and other forms of interaction
Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.
Interactions
Enzyme inducers
Interactions can occur with medicinal products that induce microsomal enzymes (especially cytochrome P450 3A4) which can result in increased clearance of sex hormones and which may lead to breakthrough bleeding and/or contraceptive failure.
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 medication therapy enzyme induction may be sustained for about 4 weeks.
Women on short term treatment with any of these medicinal products should temporarily use a barrier method in addition to the COC or choose another method of contraception. The barrier method should be used during the time of concomitant medicinal product administration and for 28 days after their discontinuation. If the period during which the barrier method is used runs beyond the end of a pack, the next pack should be started without a break. In this situation, a withdrawal bleed should not be expected until the end of the second pack. If the patient does not have a withdrawal bleed during the tablet-free interval following the end of the second pack, the possibility of pregnancy must be ruled out before resuming with the next pack.
For women receiving long-term therapy with enzyme inducers, another method of contraception should be used.
The following have been shown to have clinically important interactions with Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg:
Antiretroviral agents:
ritonavir;
nelfinavir;
nevirapine.
Note: There are other antiretroviral agents that may increase plasma concentration of sex hormones.
Anticonvulsants
barbiturates (including phenobarbitone);
primidone;
phenytoin;-
carbamazepine;
oxcarbazepine;
felbamate;
topiramate.
Antibiotics/antifungals
griseofulvin;
rifampicin.
Herbal remedies
St John's wort (Hypericum perforatum)
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 oestrogen 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.
Effects on other drugs
Oral contraceptives and oestrogen/progestogen combinations like Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg may affect the metabolism of certain other drugs. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporin) or decrease (e.g. lamotrigine).
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.
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, Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg users must switch to an alternative method of contraception (e.g., progestagen-only contraception or non-hormonal methods) prior to starting therapy with this combination drug regimen. Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg can be restarted 2 weeks following completion of treatment with this combination drug regimen.
Other forms of interactions:
Laboratory tests
The use of oral contraceptives may influence the results of certain laboratory tests including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of carrier proteins and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Laboratory staff should therefore be informed about oral contraceptive use when laboratory tests are requested.
4.6 Fertility, pregnancy and lactation
Pregnancy
Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg is not indicated during pregnancy. If pregnancy occurs during treatment with Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg, further intake must be stopped.
Animal studies have revealed that feminisation of male foetuses may occur if cyproterone acetate is administered during the phase of embryogenesis at which differentiation of the external genitalia occurs. Although the results of these tests are not necessarily relevant to man, the possibility must be considered that administration of Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg to women after the 45th day of pregnancy could cause feminisation of male foetuses. It follows from this that pregnancy is an absolute contraindication for treatment with Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg, and must be excluded before such treatment is begun
Breast-feeding
The use of Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg during lactation may lead to a reduction in the volume of milk produced and to a change in its composition. Minute amounts of the active substances are excreted with the milk. These amounts may affect the child particularly in the first 6 weeks post-partum. Mothers who are breast-feeding should be advised not to take Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg until the nursing mother has weaned her child off breast milk.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive or operate machines have been performed.
4.8 Undesirable effects
Summary of the safety profile
The most commonly reported adverse reactions with Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg are nausea, abdominal pain, increased weight, headache, depressed mood, altered mood, breast pain, breast tenderness. They occur in > 1 % to <10% of the users.
There is an increased risk of thromboembolism for all women who use cyproterone acetate/ethinylestradiol (see section 4.4).
Adverse reactions are listed according to MedDRA frequency convention and system organ class database.
| System Organ Class | Common (> 1/100 to <1/10) | Uncommon (> 1/1,000 to <1/100) | Rare (> 1/10,000 to < 1/1,000) | Not known (cannot be estimated from the available data) |
| Immune system disorders | hypersensitivity | Exacerbation of hereditary angioedema | ||
| Metabolism and nutrition disorders | fluid retention | hypertriglyceridemia | ||
| Psychiatric disorders | depressed mood, mood | libido decreased | libido increased |
| altered | ||||
| Nervous system disorders | headache | migraine | exacerbation of chorea | |
| Eye disorders | contact lens intolerance | |||
| Vascular Disorders | Thromboembolism | Increased blood pressure | ||
| Gastrointestinal disorders | nausea, abdominal pain | vomiting, diarrhoea | Crohn's disease, ulcerative colitis | |
| Hepatobiliary disorders | liver function disturbances | |||
| Skin and subcutaneous tissue disorders | rash, urticaria | erythema nodosum, erythema multiforme | Chloasma | |
| Reproductive system and breast disorders | breast pain, breast tenderness | breast hypertrophy | vaginal discharge, breast discharge | reduced menstrual flow, spotting, breakthrough bleeding and missed withdrawal bleeding, post pill amenorrhoea |
| Investigations | weight increased | weight decreased |
Description of selected adverse reactions
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.
The following serious adverse events have been reported in women using cyproterone acetate/ethinylestradiol, which are discussed in section 4.4:
Venous thromboembolic disorders
Arterial thromboembolic disorders
Hypertension
Liver tumours (benign and malignant)
Occurrence or deterioration of conditions for which association with COC use is not conclusive: Crohn's disease, ulcerative colitis, jaundice and/or pruritus related to cholestasis; gallstone formation; systemic lupus erythematosus; herpes gestationis; otosclerosis-related hearing loss; porphyria; cervical cancer; haemolytic uremic syndrome; Sydenham's chorea; epilepsy.
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 oestrogens may induce or exacerbate symptoms of angioedema
The frequency of diagnosis of breast cancer is very slightly increased among OC 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 or cyproterone acetate/ethinylestradiol use is unknown. For further information, see sections 4.3 and 4.4.
Changes in glucose tolerance or effect on peripheral insulin resistance have been reported in women using COCs or cyproterone acetate/ethinylestradiol (see section 4.4).
Interactions
Breakthrough bleeding and/or contraceptive failure may result from interactions of other medicinal products (enzyme inducers) with oral contraceptives (see section 4.5).
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 Yellow Card Scheme: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Overdose may cause nausea, vomiting and, in females, withdrawal bleeding. Withdrawal bleeding may even occur in girls before their menarche, if they accidentally take the medicinal product.
There are no specific antidotes and further treatment should be symptomatic.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiandrogens and oestrogens
ATC code: G03HB01
Cyproterone acetate/ethinylestradiol blocks androgen-receptors. It also reduces androgen synthesis both by a negative feedback effect on the hypothalamo-pituitiary-ovarian systems and by the inhibition of androgen-synthesising enzymes.
Although cyproterone acetate/ethinylestradiol also acts as an oral contraceptive, it is not recommended in women solely for contraception, but should be reserved for those women requiring treatment for the androgendependent skin conditions described.
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 doseresponse relationship was demonstrated.
| Cumulative dose of cyproterone acetate | Incidence rate (in patient-years) | HRadj (95% CI) a |
| 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 propertiesCyproterone acetate
Following oral administration cyproterone acetate is completely absorbed over a wide dose range. The ingestion of 2 mg cyproterone acetate in combination with 0.035 mg of ethinylestradiol gave a maximum serum level of 15 ng cyproterone acetate/ml at 1.6 hours.
Distribution
Thereafter active substance serum levels decrease in two disposition phases characterised by half-lives of 0.8 hours and 2.3 days. The total clearance of cyproterone acetate from serum was determined to be 3.6 ml/min/kg.
Biotransformation
Cyproterone acetate is metabolised by various pathways including hydroxylations and conjugations. The main metabolite in human plasma is the 15-hydroxy derivative.
Elimination
Some of the dose was excreted unchanged with the bile fluid. Most of the dose is excreted in the form of metabolites at a urinary to biliary ratio of 3:7. The renal and biliary excretion was determined to proceed with half-life of 1.9 days. Metabolites from plasma were eliminated at a similar rate (half-life of 1.7 days). Cyproterone acetate is almost exclusively bound to plasma albumin only about 3.5–4.0 % of total active substance levels are present unbound. Because protein binding is non-specific, changes in sex hormone binding globulin (SHBG) levels do not affect cyproterone acetate pharmacokinetics.
According to the long half-life of the terminal disposition phase from plasma (serum) and the daily intake, cyproterone acetate accumulates during one treatment cycle. Mean maximum active substance serum levels increased from 15 ng/ml (day 1) to 21 ng/ml and 24 ng/ml at the end of the treatment cycles 1 and 3 respectively. The area under the concentration versus time profile increased 2.2 fold (end of cycle 1) and 2.4 fold (end of cycle 3). Steady state conditions were reached after about 16 days. During long term treatment cyproterone acetate accumulates over treatment cycles by a factor of 2.
The absolute bioavailability of cyproterone acetate is almost complete (88 % of dose). The relative bioavailability of cyproterone acetate (in combination with 0.035 mg of ethinylestradiol) was 109 % when compared to an aqueous microcrystalline suspension.
Absorption
Orally administered ethinylestradiol is rapidly and completely absorbed. Following ingestion of 0.035 mg of ethinylestradiol in combination with 2 mg of cyproterone acetate, maximum active substance serum levels of about 80 pg/ml are reached at 1.7 hours. Thereafter ethinylestradiol plasma levels decrease in two phases characterised by half-lives of 1–2 hours and about 20 hours. For analytical reasons these parameters can only be calculated for higher doses.
For ethinylestradiol an apparent volume of distribution of about 5 l/kg and a metabolic clearance rate from plasma of about 5 ml/min/kg were determined.
Biotransformation
Ethinylestradiol is highly, but non-specifically bound to serum albumin only 2 % of the active substance levels are present unbound. During absorption and first liver passage ethinylestradiol is metabolised resulting in a reduced absolute and variable oral bioavailability.
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.
Elimination
Unchanged drug is not excreted. Ethinylestradiol metabolites are excreted at a urinary to biliary ratio of 4:6 with a half-life of about 1 day.
Steady-state conditions
According to the half-life of the terminal disposition phase from plasma and the daily ingestion, steady state plasma levels are reached after 3–4 days and are higher by 3040 % as compared to a single dose. The relative bioavailability (reference: aqueous microcrystalline suspension) of ethinylestradiol was almost complete.
The systemic bioavailability of ethinylestradiol might be influenced in both directions by other drugs. There is, however, no interaction with high doses of vitamin C.
Ethinylestradiol induces the hepatic synthesis of SHBG and corticosteroid binding globulin (CBG) during continuous use. The extent of SHBG induction, however, is dependent upon the chemical structure and dose of the co-administered progestin.
During the treatment with cyproterone acetate/ethinylestradiol SHBG concentrations in serum increased from about 100 nmol/l to 300 nmol/l and the serum concentrations of CBG were increased from about 50 Lig/ml to 95 gg/ml.
5.3 Preclinical safety dataEthinylestradiol
The toxicity profile of ethinylestradiol is well known. There are no preclinical data of relevance to the prescriber that provide additional safety information to those already included in other sections of the product information.
Systemic toxicity
Preclinical safety data reveal no specific risk for humans based on conventional studies of repeated dose toxicity.
Embryotoxicity/teratogenicity
Investigations into embryotoxicity using the combination of the two active ingredients showed no effects indicative of a teratogenic effect following treatment during organogenesis before development of the external genital organs.
Administration of cyproterone acetate during the hormone-sensitive differentiation phase of the genital organs led to signs of feminization in male fetuses following higher doses. Observation of male newborn children who had been exposed in utero to cyproterone acetate did not show any signs of feminization. However, pregnancy is a contraindication for the use of {Nationally completed name}.
Recognized first-line tests of genotoxicity gave negative results when conducted with cyproterone acetate. However, further tests showed that cyproterone acetate was capable of producing adducts with DNA (and an increase in DNA repair activity) in liver cells from rats and monkeys and also in freshly isolated human hepatocytes, the DNA-adduct level in dog liver cells was extremely low.
This DNA-adduct formation occurred at systemic exposures that might be expected to occur in the recommended dose regimens for cyproterone acetate. In vivo consequences of cyproterone acetate treatment were the increased incidence of focal, possibly pre-neoplastic, liver lesions in which cellular enzymes were altered in female rats, and an increase of mutation frequency in transgenic rats carrying a bacterial gene as target for mutations.
Clinical experience and well conducted epidemiological trials to date would not support an increased incidence of hepatic tumors in man. Nor did investigations into the tumorigenicity of cyproterone acetate in rodents reveal any indication of a specific tumorigenic potential.
However, it must be borne in mind that sexual steroids can promote the growth of certain hormone-dependent tissues and tumors.
On the whole, the available findings do not raise any objection to the use of cyproterone acetate/ethinylestradiol in humans if used in accordance with the directions for the given indication and at the recommended dose.
PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Lactose monohydrate
Maize starch
Povidone K25
Talc
Magnesium stearate
Tablet coating:
Sucrose
Calcium carbonate
Talc
Polyethylene glycol 6000
Povidone K90
Titanium dioxide (E 171)
Glycerol 85%
Montan glycol wax
Iron oxide yellow (E 172)
6.2 Incompatibilities
Not applicable
6.3 Shelf life
2 years
6.4 Special precautions for storage
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
The coated tablets are packed in PVC/Aluminium blisters or PVC/PVCD/ Aluminium blisters and inserted in a carton.
Blister: 1×21, 3×21, 6×21, 13×21 coated tablets
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
6.6 Special precautions for disposal and other handlingAny unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Sandoz Limited
Frimley Business Park
Frimley
Camberley
Surrey
GU16 7SR
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 04416/1040
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION
03/02/2009