Co-Cyprindiol 2000/35 Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
V This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
1 NAME OF THE MEDICINAL PRODUCT
CAMILETTE®
Co-cyprindiol 2000/35 Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 2 milligrams of the anti-androgen, cyproterone acetate and 35 micrograms of the oestrogen, ethinylestradiol. For excipients see Section 6.1.
3 PHARMACEUTICAL FORM
Sugar-coated tablets
Beige to pale yellow, biconvex, round shiny tablets.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of moderate to severe acne related to androgen-sensitivity (with or without seborrhea) and/or hirsutism in women of reproductive age. For the treatment of acne, CAMILETTE® should only be used after topical therapy or systemic antibiotic treatments have failed.
Since CAMILETTE® 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
CAMILETTE® inhibits ovulation and thereby prevents conception. Patients who are using CAMILETTE® 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.
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.
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 seven tablet-free days have followed the preceding course.
When the contraceptive action of CAMILETTE® 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 CAMILETTE®, follow the instructions given below:
Changing from 21-day combined oral contraceptives: The first tablet of CAMILETTE® 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): CAMILETTE® should be started after taking the last active tablet from the Every Day Pill pack. The first CAMILETTE® tablet is taken the next day. Additional contraceptive precautions are not then required.
Changing from a progestogen-only pill (POP): The first tablet of CAMILETTE® 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. Postpartum and post-abortum use: After pregnancy, CAMILETTE® can be started 21 days after vaginal delivery, provided that the patient is fully ambulant and there are no puerperal complications. Additional contraceptive precautions will be required for the first seven 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 contraindicated with CAMILETTE®. After a first-trimester abortion, CAMILETTE® may be started immediately in which case no additional contraceptive precautions are required.
Special circumstances requiring additional contraception:
Incorrect administration: 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 seven days, while the next seven tablets are being taken. Additionally, therefore, if tablet(s) have been missed during the last seven 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 seven days following the upset. If these seven 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.
Complete remission of acne is to be expected in nearly all cases, often within a few months, 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 weeks after the indicated condition(s) has/have completely resolved and that CAMILETTE® is not continued solely to provide oral contraception. Repeat courses of CAMILETTE® may be given if the androgen-dependent condition(s) recur.
4.3 Contraindications
CAMILETTE® must not be taken if the patient has any of the following
conditions:
• 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)
• Pregnancy or lactation.
• Severe disturbances of liver function, jaundice or persistent itching during a previous pregnancy, Dubin-Johnson syndrome, Rotor syndrome, previous or existing liver tumours.
• 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).
• Current venous thrombotic or embotic processes.
• Existing or previous arterial thrombotic or embolic processes.
• Abnormal red blood cells (Sickle-cell anaemia).
• Cancer of the breast or endometrial cancer, or a history of these conditions.
• Disorders of lipid metabolism.
• History of herpes gestationis.
• Deterioration of otosclerosis during pregnancy.
• Undiagnosed abnormal vaginal bleeding.
Hypersensitivity to any of the ingredients of CAMILETTE® Co-cyprindiol 2000/35 Tablets.
4.4 Special warnings and precautions for use
Warnings:
Patients with rare hereditary problems of fructose intolerance, galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption, or sucrose-isomaltase insufficiency should not take this medicinal product.
Like many other steroids, CAMILETTE®, 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.
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 CAMILETTE®. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, a liver tumour should be included in the differential diagnosis.
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 CAMILETTE® 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 CAMILETTE®, and must be excluded before such treatment is begun.
CAMILETTE® is composed of the progestogen cyproterone acetate and the oestrogen ethinylestradiol and is administered for 21 days of a monthly cycle.
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).
It therefore has a similar composition to that of a combined oral contraceptive (COC). The use of any COC or CAMILETTE® carries an increased risk for venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, compared with no use. The excess risk of VTE is highest during the first year a woman uses a COC. This increased risk is less than the risk of VTE associated with pregnancy, which is estimated as 60 per
100.000 pregnancies.
Full recovery from such disorders does not always occur; VTE is fatal in 1-2% of cases.
Epidemiological studies have shown that the incidence of VTE in users of oral contraceptives with low oestrogen content (<50 micrograms ethinylestradiol) is up to 40 cases per 100,000 women-years. This compares with 5-10 cases per
100.000 women-years for non-users.
Certain factors may increase the risk of venous thrombosis, e.g., severe obesity (body mass index >30kg/m2), increasing age, a genetic predisposition to clotting or a personal or family history of confirmed, idiopathic VTE (where family history refers to VTE in a sibling or a parent at a relatively early age, see contraindications section 4.3). In addition, the risk of VTE may be temporarily increased by prolonged immobilisation, major surgery, any surgery to the legs, or major trauma (see "Reasons for stopping CAMILETTE® immediately").
There is some epidemiological evidence that the incidence of VTE is higher in users of CAMILETTE® when compared to users of COCs with low oestrogen content (<50 micrograms).
The user group of CAMILETTE® as a treatment for severe 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.
Epidemiological studies have also associated the use of COCs with an increased risk of arterial (myocardial infarction, transient ischaemic attack) thromboembolism. Certain factors such as smoking, obesity, cardiovascular disease, hypertension, diabetes and migraine may increase the risk of arterial thromboembolism. The risk of arterial thrombosis associated with oral contraceptives increases with age, and cigarette smoking aggravates this risk.
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 combined oral contraceptives offer substantial protection against both ovarian and endometrial cancer.
An increased risk of cervical cancer in long-term users of combined oral contraceptives has been reported in some studies, but there continues to be controversy about the extent to which this is attributable to the confounding effects of sexual behaviour and other factors.
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 5 years of use and up to 10 years after stopping COCs, compared with numbers of breast cancers diagnosed in 10,000 women who have never used COCs.
The possibility cannot be ruled out that certain chronic diseases may occasionally deteriorate during the use of CAMILETTE® (see Precautions).
Reasons for stopping CAMILETTE® immediately
• First signs of thrombophlebitis or thromboembolic symptoms, e.g. sudden severe pain or tightness in the chest; sudden breathlessness or stabbing pains on breathing or coughing for no apparent reason; severe pain in or swelling of the leg(s).
• Serious effects of the nervous system, including unusual severe or frequent headaches, especially if for first time, or exacerbation of existing migrainous headaches. Sudden partial or complete loss of vision, or sudden disturbance of hearing or speech. Fainting attacks or collapse, or increase in epileptic seizures.
• Hepatitis (inflammation of liver), jaundice, liver enlargement, itching of the whole body.
• Severe depression.
• Significant rise in blood pressure, systolic above 160 mmHg and diastolic above 100 mmHg.
• Severe upper abdominal pain or liver enlargement.
• 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 two weeks after full ambulation. In case of emergency surgery, thrombotic prophylaxis is usually indicated, e.g. subcutaneous heparin.
• Clear worsening of conditions known to deteriorate during use of hormonal contraception or during pregnancy.
• Pregnancy is a reason for stopping immediately because it has been suggested by some investigations that oral contraceptives taken in early pregnancy may slightly increase the risk of foetal malformations. Other investigations have failed to support these findings. The possibility therefore cannot be excluded, but it is certain that, if a risk exists at all, it is very small.
Circulatory disorders
• The use of CAMILETTE® 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 CAMILETTE® 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 CAMILETTE® 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 CAMILETTE® 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 CAMILETTE®);
- 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 CAMILETTE® 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 CAMILETTE®);
- 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 (for information on ‘Pregnancy and lactation’ see section 4.6).
• An increase in frequency or severity of migraine during use of CAMILETTE® (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of CAMILETTE®.
• Women using CAMILETTE® should be specifically pointed out to contact their physician in case of possible symptoms of thrombosis. In case of suspected or confirmed thrombosis, CAMILETTE® use should be discontinued. Adequate contraception should be initiated because of the teratogenicity of anti-coagulant therapy (coumarins).
Precautions:
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 the 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.
If any of the conditions/risk factors mentioned below is present, the benefits of the use of CAMILETTE® should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start using CAMILETTE® 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 CAMILETTE® should be discontinued:
Diabetes mellitus, or a tendency towards diabetes mellitus (e.g. unexplained glycosuria), hypertension, varicose veins, a history of phlebitis, otosclerosis, multiple sclerosis, epilepsy, porphyria, tetany, disturbed liver function, Sydenham's chorea, renal dysfunction, family history of clotting disorders, obesity, family history of breast cancer and patient history of benign breast disease, clinical depression, systemic lupus erythematosus, uterine fibroids, an intolerance to contact lenses, migraine, gall-stones, cardiovascular diseases, chloasma, asthma or any disease that is prone to worsen during pregnancy.
Patients with a history of depression or any condition mentioned above should be monitored during treatment with CAMILETTE®.
It should be borne in mind that the use of ultraviolet lamps, for the treatment of acne, or prolonged exposure to sunlight, increases the risk of the deterioration of chloasma.
If CAMILETTE® is discontinued; other methods of contraception should be introduced if needed.
Some women may experience amenorrhoea or oligomenorrhoea after discontinuation of CAMILETTE®, especially when these conditions existed prior to use. Women should be informed of this possibility.
4.5 Interaction with other medicinal products and other forms of interaction
The effectiveness of oral contraceptives may be considerably reduced by interaction with drugs that induce hepatic enzyme activity (e.g. barbiturates, carbamazepine, griseofulvin, modafinil, nelfinavir, nevirapine, oxcarbazepine, phenytoin, phenylbutazone, phenobarbital, primidone, ritonavir, topiramate, and, above all, rifabutin and rifampicin); advice on the possibility of interaction with newer antiretroviral drugs should be sought from HIV specialists.
Women receiving short courses of enzyme-inducers and broad-spectrum antibiotics should take additional, non-hormonal (except rhythm or temperature method) contraceptive precautions during the time of concurrent medication and for seven days afterwards. If these seven days over-run 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.
The possibility cannot be ruled out that oral tetracyclines, if used in conjunction with CAMILETTE® tablets may reduce its contraceptive efficacy, although it has not been shown. When drugs of these classes are being taken it is, therefore, advisable to use additional non-hormonal methods of contraception (except rhythm or temperature methods) since an extremely high degree of protection must be provided when CAMILETTE® is being taken. With rifampicin, additional contraceptive precautions should be continued for at least four weeks after treatment stops, even if only a short course was administered.
The requirement for oral antidiabetics or insulin can change as a result of the effect on glucose tolerance.
The herbal remedy St. John’s Wort (Hypericum perforatum) should not be taken concomitantly with CAMILETTE® as this could potentially lead to a loss of contraceptive effect.
4.6 Fertility, Pregnancy and lactation
Contraindicated.
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 CAMILETTE® 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 CAMILETTE®, and must be excluded before such treatment is begun.
4.7 Effects on ability to drive and use machines
None known
4.8 Undesirable effects
There is an increased risk of venous thromboembolism for all women who use CAMILETTE®. (See section 4.4).
Nervous system disorders
In rare cases, headaches, changes in libido and depressive moods can occur. Post-marketing reports of severe depression in patients using Co-cyprindiol have been received. However, a causal relationship between clinical depression and Co-cyprindiol has not been established.
Respiratory, thoracic and mediastinal disorders In rare cases, breast tenderness can occur.
Gastrointestinal disorders
In rare cases, gastric upsets, nausea and vomiting can occur.
Skin and subcutaneous tissue disorders
In predisposed women, it can sometimes cause chloasma, which is exacerbated by exposure to sunlight. Such women should avoid prolonged exposure to sunlight.
Blood and the lymphatic system disorders
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.
Reproductive system and breast disorders Menstrual changes:
(1) 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.
(2) 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:
"Spotting" or heavier "breakthrough bleeding" sometimes occurs during tablet taking, especially in the first few cycles, and normally ceases spontaneously. CAMILETTE® should therefore, be continued even if irregular bleeding occurs. If irregular bleeding is persistent, appropriate diagnostic measures to exclude an organic cause are indicated and may include curettage. This also applies in the case of spotting which occurs at regular intervals in several consecutive cycles or which occurs for the first time after long use of CAMILETTE®.
General disorders and administration site conditions Individual cases of poor tolerance of contact lenses have been reported with use of oral contraceptives. Contact lens wearers who develop changes in lens tolerance should be assessed by an ophthalmologist.
Vascular disorders
In rare cases thromboembolism may occur
The following serious adverse events have been reported in women using CAMILETTE®, which are discussed in section 4.4 Special warning and precautions for use:
• Venous thromboembolic disorders
• Arterial thromboembolic disorders
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. There are no specific antidotes and further treatment should be symptomatic.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC Code: G03H B01 Group: Anti-androgens and estrogens.
CAMILETTE® 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 CAMILETTE® 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 an essentially similar product to CAMILETTE® effects a maximum serum level of 15 nanograms cyproterone acetate/ml at 1.6 hours. Thereafter drug 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 P-hydroxy derivative.
Some dose parts are 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 a 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 15 nanograms/ml (day 1) to 21 nanograms/ml and 24 nanograms/ml at the end of treatment cycles one and three respectively. The area under the concentration versus time profile increased 2.2 fold (end of cycle one) and 2.4 fold (end of cycle three). Steady state conditions were reached after about 16 days.
During long term treatment cyproterone acetate accumulates over treatment cycles by a factor of two.
The absolute bioavailability of cyproterone acetate is almost complete (88% of dose). The relative bioavailability of cyproterone acetate from an essentially similar product to CAMILETTE® was 109% when compared to an aqueous microcrystalline suspension.
Ethinylestradiol: Orally administered ethinylestradiol is rapidly and completely absorbed. Following ingestion of an essentially similar product to CAMILETTE®, maximum drug serum levels of about 80 picograms/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 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 one day.
According to the half-life of the terminal disposition phase from plasma and the daily ingestion steady state plasma levels are reached after three - four 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 an essentially similar product to CAMILETTE®, 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 micrograms/ml to 95 micrograms/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 Maize starch Povidone Talc
Magnesium stearate (E 572) Sucrose Macrogol 6000 Calcium carbonate (E170)
Titanium dioxide (E171)
Glycerol 85%
Montan glycol wax
Yellow ferric oxide pigment (E172)
6.2 Incompatibilities
Not applicable
6.3 Shelf life
Two years
6.4 Special precautions for storage
No special storage conditions.
6.5 Nature and contents of container
Outer carton contains aluminium foil and PVC blister calendar packs each comprising 21 tablets. Each carton contains three blister calendar packs.
6.6 Special precautions for disposal
Keep out of the sight and reach of children.
7 MARKETING AUTHORISATION HOLDER
Chelonia Healthcare Limited
11 Boumpoulinas Street, 3rd Floor, 1060 Nicosia Cyprus
8 MARKETING AUTHORISATION NUMBER(S)
PL 33414/0142
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
15/04/2005
10 DATE OF REVISION OF THE TEXT
05/12/2014