Co-Cyprindiol 2000/35 Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Co-cyprindiol 2000/35 Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains cyproterone acetate 2000 micrograms and ethinylestradiol 35 micrograms.
Excipient with known effect:
Each film-coated tablet contains 36.77 mg of lactose For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
Yellow, round biconvex tablets.
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, Co-cyprindiol should only be used after topical therapy or systemic antibiotic treatments have failed.
Since Co-cyprindiol 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
Posology Dosage regimen
Co-cyprindiol inhibits ovulation and thereby prevents conception. Patients who are using Co-cyprindiol should not therefore use an additional hormonal contraceptive, as this will expose the patient to an excessive dose of hormones and is not necessary for effective contraception.
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).
Subsequent courses
Each subsequent course is started after 7 tablet-free days have followed the preceding course.
When the contraceptive action of Co-cyprindiol 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 Co-cyprindiol, follow the instructions given below:
Changing from 21-day combined oral contraceptives
The first tablet of Co-cyprindiol 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)
Co-cyprindiol should be started after taking the last hormone containing tablet from the Every Day Pill pack. The first Co-cyprindiol tablet is taken the next day. Additional contraceptive precautions are not then required.
Changing from a progestogen-only pill (POP)
The first tablet of Co-cyprindiol 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, Co-cyprindiol 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 Co-cyprindiol. After a first-trimester abortion, Co-cyprindiol 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.
Special circumstances requiring additional contraception
A single delayed tablet should be taken as soon as possible, and if this can be done 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, and 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.
Gastro-intestinal 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 gastro-intestinal 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 gastro-intestinal disorder is likely to be prolonged.
Additional information on special populations Paediatric population
Co-cyprindiol is only indicated after menarche Elderly patients
Not applicable. Co-cyprindiol is not indicated after menopause.
Hepatic impairment
Co-cyprindiol is contraindicated in women with severe hepatic disease as long as liver function values have not returned to normal (see section 4.3).
Renal impairment
Co-cyprindiol 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.
• 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).
• Personal or family history of confirmed, idiopathic venous thromboembolism (VTE) (where a family history refers to VTE in a sibling or parent at a relatively early age).
• 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).
• The presence of a severe or multiple risk factor(s) for venous or arterial thrombosis (see section 4.4.) such as:
o diabetes mellitus with vascular symptoms o severe hypertension o severe dyslipoproteinaemia
• Sickle-cell anaemia.
• Mammary or endometrial carcinoma, or a history of these conditions.
• Disorders of lipid metabolism.
• History of herpes gestationis.
• Deterioration of otosclerosis during pregnancy.
• Undiagnosed abnormal vaginal bleeding.
• Current or history of breast cancer.
• Hypersensitivity to the cyproterone acetate or ethinylestradiol or to any of the excipients listed in section 6.1.
• Concomitant use with another hormonal contraceptive (see section 4.1)
• Presence or history of cerebrovascular accident
• 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)
• History of migraine with focal neurological symptoms.
Relevant UK clinical guidance on combined oral contraceptives (COCs) should also be consulted.
Co-cyprindiol is not for use in men.
4.4 Special warnings and precautions for use
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/ethinylestradiol confer protective effects to the same level.
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/ethinylestradiol. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, a liver tumour should be included in the differential diagnosis.
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 continues to be controversy about the extent to which this is attributable to the confounding effects, e.g. cervical screening and sexual behaviour including use of barrier contraceptives.
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 (see bar chart).
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).
Estimated cumulative numbers of breast cancers per 10.000 women diagnosed in 5years of use and up to 10 years afterstopping COCs, compared with numbers of breast cancers diagnosed in 10:00 0 womenwho had neverused COCs
300 n
262
230
30-34 3E-33 40^4
+6 50 65
Other conditions
The possibility cannot be ruled out that certain chronic diseases may occasionally deteriorate during the use of cyproterone acetate/ethinylestradiol.
Known hyperlipidaemias
Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs or cyproterone acetate/ethinylestradiol.
Women with hyperlipidaemias are at an increased risk of arterial disease (see section 4.4 'Circulatory disorders'). However routine screening of women on COCs or cyproterone acetate/ethinylestradiol 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 oestrogen/progestogen combinations like cyproterone acetate/ethinylestradiol, clinically relevant increases are rare. However, if sustained hypertension develops during the use of cyproterone acetate/ethinylestradiol, antihypertensive treatment should normally be instigated at a level of 160/100 mm Hg in uncomplicated patients or at 140/90 mm Hg in those with target organ damage, established cardiovascular disease, diabetes or with increased cardiovascular risk factors. Decisions about the continued use of cyproterone
acetate/ethinylestradiol, should be made at lower BP levels, and alternative contraception may be advised.
Conditions which deteriorate with pregnancy or during previous COC or cyproterone acetate/ethinylestradiol 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/ethinylestradiol. Consideration should be given to stopping cyproterone acetate/ethinylestradiol if any of the following occur during use:
• jaundice and/or pruritus related to cholestasis
• COCs or cyproterone acetate/ethinylestradiol may increase the risk of gallstone formation and may worsen existing disease
• systemic lupus erythematosus
• herpes gestationis
• otosclerosis-related hearing loss
• sickle cell anaemia
• renal dysfunction
• hereditary angioedema
• any other condition an individual woman has experienced worsening of during pregnancy or previous use of COCs or cyproterone acetate/ethinylestradiol.
Disturbances of liver function
Acute or chronic disturbances of liver function may necessitate the discontinuation of COC or cyproterone acetate/ethinylestradiol use until markers of liver function return to normal.
Diabetes (without vascular involvement)
Insulin-dependent diabetics without vascular disease can use cyproterone acetate/ethinylestradiol. 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/ethinylestradiol. Diabetics with existing vascular disease are contraindicated from using cyproterone acetate/ethinylestradiol (see section 4.3).
Although COCs or oestrogen/progestogen combinations like cyproterone acetate/ethinylestradiol 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/ethinylestradiol.
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/ethinylestradiol.
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 nonhormonal 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/ethinylestradiol, especially when these conditions existed prior to use. Women should be informed of this possibility.
Reasons for stopping cyproterone acetate/ethinylestradiolimmediately:
When stopping oral contraception nonhormonal 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 ‘conditions which deteriorate in pregnancy or during previous COC use’ under ‘other conditions’).
10. Pregnancy is a reason for stopping immediately (see section 4.6).
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 medicinal 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
Co-cyprindiol 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).
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).
Women should be advised that cyproterone acetate/ethinylestradiol 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/ethinylestradiol should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start using cyproterone acetate/ethinylestradiol. 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/ethinylestradiol 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 94 mm Hg (see also section 4.4 'Reasons for stopping cyproterone acetate/ethinylestradiol 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/ethinylestradiol.
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/ethinylestradiol);
- 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/ethinylestradiol has not been discontinued in advance.
- obesity (body mass index over 30 kg/m ).
• 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/ethinylestradiol);
- 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, hemolytic 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 (see section 4.6).
An increase in frequency or severity of migraine during use of cyproterone acetate/ethinylestradiol (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of cyproterone acetate/ethinylestradiol.
Women using cyproterone acetate/ethinylestradiol 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/ethinylestradiol use should be discontinued. Adequate contraception should be initiated because of the teratogenicity of anti-coagulant therapy (coumarins).
Other factors affecting circulatory events
The user group of cyproterone acetate/ethinylestradiol as a treatment for acne or moderately severe hirsutism is likely to include patients that may have an inherently increased cardiovascular risk such as that associated with polycystic ovarian syndrome.
Biochemical factors that may be indicative of hereditary or acquired predisposition for venous or arterial thrombosis include Activated Protein C (APC) resistance, hyperhomocysteinaemia, antithrombin-III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).
When considering risk/benefit, the physician should take into account that adequate treatment of a condition may reduce the associated risk of thrombosis and that the risk associated with pregnancy is higher than that associated with COC or cyproterone acetate/ethinylestradiol use.
Excipient
Each tablet of this medicinal product contains 36.77 mg lactose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucosegalactose malabsorption should not take this medicine
4.5 Interaction with other medicinal products and other forms of interaction
Enzyme inducers
Interactions can occur with drugs 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.
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 drug 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/ethinylestradiol:
Anticonvulsants
Barbiturates (including phenobarbitone), primidone, phenytoin, carbamazepine, oxcarbazepine, topiramate.
Antibiotics/antifungals
Griseofulvin, rifampicin.
Herbal remedies
St John's wort (Hypericum perforatum).
Antiretroviral agents Ritonavir, nelfinavir, nevirapine.
Note: There are other antiretroviral agents that may increase plasma concentration of sex hormones.
Effects on other drugs
Oral contraceptives and oestrogen/progestogen combinations like cyproterone acetate/ethinylestradiol may affect the metabolism of certain other drugs. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporin) or decrease (e.g. lamotrigine).
Note: The prescribing information of concomitant medications should be consulted to identify potential 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
Pregancy
Cyproterone acetate/ethinylestradiol is not indicated during pregnancy. If pregnancy occurs during treatment with cyproterone acetate/ethinylestradiol, 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/ethinylestradiol to women after the 45th day of pregnancy could cause feminisation of male foetuses. It follows from this that pregnancy is an absolute contra-indication for treatment with cyproterone acetate/ethinylestradiol, and must be excluded before such treatment is begun.
Breast-feeding
The use of cyproterone acetate/ethinylestradiol 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/ethinylestradiol until the nursing mother has weaned her child off breast milk.
Fertility
There is no relevant data to demonstrate the effect of cyproterone acetate/ethinylestradiol on human fertility.
4.7 Effects on ability to drive and use machines
Not relevant.
4.8 Undesirable effects
|
System Organ Class |
Adverse events reported in clinical trials |
Adverse events reported post marketing | ||
|
Common |
Uncommon |
Rare | ||
|
(> 1/100) |
(> 1/1,000 to <1/100) |
(> 1/10,000 to < 1/1000) | ||
|
Eye disorders |
contact lens intolerance | |||
|
Gastrointestinal disorders |
nausea, abdominal pain |
vomiting, diarrhea | ||
|
Immune system disorders |
hypersensitivity |
exacerbation of hereditary angioedema | ||
|
Investigations |
weight increased |
weight decreased | ||
|
Metabolism and nutrition disorders |
fluid retention |
hypertriglyceridemia | ||
|
Nervous system disorders |
headache |
migraine |
exacerbation of chorea | |
|
Gastrointestinal disorders |
Crohn's disease, ulcerative colitis | |||
|
Hepatobiliary disorders |
liver function disturbances | |||
|
Psychiatric disorders |
depressed mood, mood altered |
libido decreased |
libido increased | |
|
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 |
|
Skin and subcutaneous |
rash, urticaria |
erythema nodosum, erythema |
chloasma | |
|
System Organ Class |
Adverse events reported in clinical trials |
Adverse events reported post marketing | ||
|
Common |
Uncommon |
Rare | ||
|
(> 1/100) |
(> 1/1,000 to <1/100) |
(> 1/10,000 to < 1/1000) | ||
|
tissue disorders |
multiforme | |||
|
Vascular disorders |
- |
- |
Thromboembolism |
Increase in blood pressure |
Post-marketing reports of severe depression (including very rare reports of suicidal ideation or behaviour) in patients using cyproterone acetate/ethinylestradiol have been received. However, a causal relationship between clinical depression and cyproterone acetate/ethinylestradiol has not been established.
There is an increased risk of thromboembolism for all women who use cyproterone acetate/ethinylestradiol (see 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
• Strokes (e.g. transient ischemic attack, ischemic stroke, haemorrhagic stroke)
• Hypertension
• Liver tumours (benign and malignant)
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.
Conditions reported to deteriorate with pregnancy or previous COC or cyproterone acetate/ethinylestradiol use
Jaundice and/or pruritus related to cholestasis; gallstone formation; systemic lupus erythematosus; herpes gestationis; otosclerosis-related hearing loss; sickle cell anaemia; renal dysfunction; hereditary angioedema; porphyria; cervical cancer.
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).
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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Overdose may cause nausea, vomiting and, in females, withdrawal bleeding. There are no specific antidotes and further treatment should be symptomatic.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiandrogens and estrogens.
ATC code: G03HB01
Cyproterone acetate/ethinylestradiol blocks androgen-receptors. It also reduces androgen synthesis both by negative feedback effect on the hypothalamo-pituitary-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 androgen-dependent skin conditions described.
5.2 Pharmacokinetic properties
Cyproterone acetate
Following oral administration cyproterone acetate is completely absorbed in a wide dose range. The ingestion of cyproterone acetate/ethinylestradiol effects a maximum serum level of l5 ng cyproterone acetate/ml at 1.6 hours.
Thereafter acrive 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. Cyproterone acetate is metabolised by various pathways including hydroxylations and conjugations. The main metabolite in human plasma is the 15^-hydroxy derivative.
Some dose parts are excreted unchanged with the bile fluid. Most of the dose is excreted in 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. About 3.5 - 4.0% of total drug 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 drug serum levels increased from l5ng/ml (day 1) to 21ng/ml and 24ng/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 from cyproterone acetate/ethinylestradiol was 109% when compared to an aqueous microcrystalline suspension.
Ethinylestradiol
Orally administered ethinylestradiol is rapidly and completely absorbed. Following ingestion of cyproterone acetate/ethinylestradiol maximum active substance serum levels of about 80pg/ml are reached at 1.7 hours. Thereafter ethinylestradiol plasma levels decrease in two phases characterised by halflives of 1 - 2 hours and about 20 hours. For analytical reasons these parameters can only be calculated for higher dosages.
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.
Ethinylestradiol is highly but non-specifically bound to serum albumin. 2% of the drug levels are present unbound. During absorption and first liver passage ethinylestradiol is metabolised resulting in a reduced absolute and variable oral bioavailability. 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.
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 30 - 40% 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 treatment with cyproterone acetate/ethinylestradiol SHBG concentrations in serum increased from about l00nmol/l to 300nmol/l and the serum concentrations of CBG were increased from about 50p,g/ml to 95p,g/ml.
5.3 Preclinical safety data
There are no preclinical safety data which could be of relevance to the prescriber and which are not already included in other relevant sections of the
SPC.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate,
Maize starch,
Povidone,
Purified talc,
Magnesium stearate,
Hypromellose,
Propylene glycol,
Quinoline yellow (E104).
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 25°C.
Store in the original package.
6.5 Nature and contents of container
Polyvinylchloride (PVC)/aluminium blister strips containing 21 tablets. Each carton contains either 1 or 3 blister strip packs.
6.6. Special precautions for disposal
7 MARKETING AUTHORISATION HOLDER
Cipla (EU) Limited
Hillbrow House
Hillbrow Road
Esher
Surrey
KT10 9NW
8 MARKETING AUTHORISATION NUMBER(S)
PL 36390/0027
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
06/03/2012
10 DATE OF REVISION OF THE TEXT
15/11/2016