Acnocin 2000/35 Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS ^ This medicinal product is subject to additional monitoring.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
Co-cyprindiol 2000/35 Tablets Acnocin 2000/35 Tablets
Cyproterone acetate/ Ethinylestradiol
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each coated tablet contains:
Cyproterone acetate 2mg Ethinylestradiol 0.035mg
Excipients: lactose monohydrate, sucrose
For full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Coated tablet.
Yellow, biconvex, round sugar-coated tablet.
4. CLINICAL PARTICULARS
4.1 Therapeutic Indications
Co-cyprindiol is indicated for use in women only for the treatment of:
- severe androgen-dependent acne, refractory to prolonged oral antibiotic therapy, or
- moderately severe hirsutism
In women requiring treatment for these conditions, Co-cyprindiol also provides contraception (see Section 4.4 Warnings and Precautions for use). It should not be used in women solely for contraception, but should be reserved for those women requiring treatment for the androgen-dependent conditions described.
4.2 Posology and method of administration
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.
Withdrawal bleeding usually occurs by 2-4 days after the last tablet. If this does not occur, it may be necessary to exclude pregnancy.
Starting tablets
No previous hormonal contraception (during the preceding month):
Tablets should be started on day 1 of the natural menstrual cycle (first day of bleeding). Tablet-taking may also be started during bleeding days 2-5, but in that case an additional non-hormonal contraceptive method is recommended for the first seven days of the first cycle.
Switch from another combined oral contraceptive, patch or vaginal ring:
Tablet should preferably be started on the day following the intake of the last active tablet of the previous combined oral contraceptive, but at the latest following the usual tablet-free or placebo-tablet interval of the previous combined oral contraceptive, or after removal of the patch or the vaginal ring. Switch from progestagen-only contraceptives (minipills, injections, implants or IUS):
The switch from minipills can be made at all times (the switch from implants or IUS on the day of its removal and from injections on the next scheduled day of injection), but the user should be advised to use a non-hormonal contraceptive method for the first seven days of tablet-taking.
After abortion during the first trimester:
Tablet-taking can be started immediately. In this case no other contraceptive method is needed.
After childbirth or abortion during the second trimester:
Breast-feeding mothers: see paragraph 4.6.
The use of the tablets should be started 21 to 28 days after childbirth or abortion during the second trimester. If tablet-taking is started later than this, an additional non-hormonal contraceptive method should be used for the first seven days of tablet-taking. However, if intercourse has already occurred, pregnancy should be excluded or the woman should wait for her first natural menstrual period before starting the first tablet.
Missing tablets:
If the patient forgets a single tablet, it should be taken within 12 hours of the correct time to maintain contraceptive protection. With larger errors, additional contraception (barrier method, such as a condom) is needed.
Handling of missed tablets may be managed by the following two basic rules:
1. Tablet-taking must never be discontinued for longer than 7 days.
2. Adequate suppression of the hypothalamic-pituitary-ovarian axis requires 7 days of uninterrupted tablet-taking.
Accordingly, the following advice can be given for daily practice:
Week 1
The woman should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take the next tablets at her usual time. In addition, a barrier method such as a condom should be used for the next 7 days. If the woman has had sexual intercourse in the 7 days before missing the tablet, the possibility of a pregnancy must be considered. The more tablets have been missed and the closer they are to the regular tablet-free break, the higher the risk of pregnancy.
Week 2
The woman should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take the next tablets at her usual time. Provided that the woman has taken her tablets correctly in the 7 days preceding the first missed tablet, there is no need to use extra contraceptive precautions. If she has not taken the tablets correctly or has missed more than one tablet, she should be advised to use extra contraceptive precautions for the next 7 days.
Week 3
The risk of reduced contraceptive reliability is imminent because of the forthcoming tablet-free break of 7 days. However, reduced contraceptive protection can still be prevented by adjusting the dosage. By adhering to the following advice, there is no need to use extra contraceptive precautions, provided that all the tablets have been taken correctly in the 7 days preceding the first missed tablet.
If this is not the case, the woman should follow the first of these two options and use extra contraceptive precautions for the next 7 days as well.
1. The woman should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take the next tablets at her usual time. The next pack is started as soon as the current pack is finished, i.e. there is no tablet-free break. There will probably be no withdrawal bleed until the end of the second pack, but the woman may experience spotting or breakthrough bleeding on tablet-taking days.
2. It is also possible to stop taking tablets from the current pack. The woman must then have a tablet-free break of 7 days, including the days she missed tablets, and then continue with the next pack.
If the woman misses several tablets and has no withdrawal bleed during the first normal tablet-free break, the possibility of a pregnancy must be considered.
Vomiting or diarrhoea:
If vomiting or diarrhoea occurs tablets should be taken at regular time periods. In addition, a supplemental non-hormonal contraceptive method should be used for the next 7 days.
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 Co-cyprindiol is not continued solely to provide oral contraception. Repeat courses of Co-cyprindiol may be given if the androgen-dependent acne recurs. In this case, an early restart of Co-cyprindiol should be considered. In case of a restart of Co-cyprindiol (following a 4 week or greater pill free interval), the increased risk of VTE should be considered (see section 4.4 Special warnings and precautions for use).
Additional information on special populations
Geriatric patients
Not applicable. Co-cyprindiol is not indicated after menopause.
Patients with hepatic impairment
Co-cyprindiol is contraindicated in women with severe hepatic diseases as long as liver function values have not returned to normal. See also section 'Contraindications'.
Patients with 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.
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.
- Hypersensitivity to cyproterone acetate, ethinylestradiol or any of the excipients of the medicinal product
- 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:
O diabetes mellitus with vascular symptoms O severe hypertension O 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).
- Severe disturbances of liver function, jaundice or persistent itching during a previous pregnancy, Dubin-Johnson syndrome, Rotor syndrome)
- The presence of a severe or multiple risk factor(s) for venous or arterial thrombosis may also constitute a contraindication (see section 4.4 Special warnings and precautions for use)
- Sickle-cell anaemia
- Abnormal vaginal bleeding of unknown cause
- History of herpes gestationis
- Deterioration of otosclerosis during pregnancy
- History of migraine with focal neurological symptoms
- 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).
- Known or suspected sex-steroid influenced malignancies (e.g. of the genital organs or the breasts)
- Porphyria
Co-cyprindiol 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.
Women should be advised that Co-cyprindiol does not protect against HIV infections (AIDS) and other sexually transmitted diseases.
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 has a similar composition to that of a combined oral contraceptive (COC).
The clinical and epidemiological experience with estrogen/progestogen combinations like Co-cyprindiol is predominantly based on combined oral contraceptives (COC). Therefore the following warnings related to COC use apply also for Co-cyprindiol.
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).
Conditions which require strict medical supervision
If any of the conditions/risk factors mentioned below is present, the benefits of the use of Co-cyprindiol should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start using Co-cyprindiol. 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 Co-cyprindiol 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 Co-cyprindiol immediately')
• clinical depression
• obesity migraine
• cardiovascular diseases
• chloasma
Patients with a history of depression or any condition mentioned above should be monitored during treatment with Co-cyprindiol.
Reasons for stopping Co-cyprindiol immediately:
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 '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) Circulatory disorders
• The use of Co-cyprindiol 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 Co-cyprindiol 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 Co-cyprindiol 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 Co-cyprindiol 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
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. Co-cyprindiol should not be prescribed in case of a negative risk benefit assessment. (see section 4.3 'Contraindications')
• 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 Co-cyprindiol
- 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 Co-cyprindiol 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 Co-cyprindiol
- 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 Co-cyprindiol (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of Co-cyprindiol.
Women using Co-cyprindiol should be specifically pointed out to contact their physician in case of possible symptoms of thrombosis. In case of suspected or confirmed thrombosis, Co-cyprindiol use should be discontinued. Adequate contraception should be initiated because of the teratogenicity of anticoagulant therapy (coumarins).
Other factors affecting circulatory events
The user group of Co-cyprindiol 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 Co-cyprindiol use.
Tumours
Like many other steroids, Co-cyprindiol, 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 Co-cyprindiol 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 Co-cyprindiol. 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 Co-cyprindiol.
Worsening of endogenous depression, of epilepsy, of Crohn's disease and of ulcerative colitis have been associated with COC use.
If in women suffering from hirsutism, symptoms have recently developed or increased substantially, the causes (androgen-producing tumor, adrenal enzyme defect) must be clarified by differential diagnosis.
Known hyperlipidaemias
Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs or Co-cyprindiol.
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 Co-cyprindiol 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 Co-cyprindiol, clinically relevant increases are rare. However, if sustained hypertension develops during the use of Co-cyprindiol, 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 Co-cyprindiol, should be made at lower BP levels, and alternative contraception may be advised.
Conditions which deteriorate with pregnancy or during previous COC or Co-cyprindiol use:
The following conditions have been reported to occur or deteriorate with both pregnancy and use of a COC or oestrogen/progestogen combinations like Co-cyprindiol, but the evidence of an association with COC use is inconclusive. Consideration should be given to stopping Co-cyprindiol if any of the following occur during use:
• jaundice and/or pruritus related to cholestasis
• COCs or Co-cyprindiol 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
• porphyria
• hemolytic uremic syndrome • Sydenham's chorea
• any other condition an individual woman has experienced worsening of during pregnancy or previous use of COCs or Co-cyprindiol.
Disturbances of liver function
Acute or chronic disturbances of liver function may necessitate the discontinuation of COC or Co-cyprindiol use until markers of liver function return to normal.
Diabetes (without vascular involvement)
Insulin-dependent diabetics without vascular disease can use Co-cyprindiol. 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 Co-cyprindiol. Diabetics with existing vascular disease are contraindicated from using Co-cyprindiol (see section 4.3 Contraindications).
Although COCs or oestrogen/progestogen combinations like Co-cyprindiol 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 Co-cyprindiol.
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 Co-cyprindiol 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 Co-cyprindiol, especially when these conditions existed prior to use. Women should be informed of this possibility.
Reduced efficacy
The contraceptive effect of Co-cyprindiol may be reduced in the event of e.g. missed tablets (see section 4.2, Posology and method of administration), gastro-intestinal disturbances (see section 4.2, Posology and method of administration) during tablet taking or concomitant medication (see section 4.5, Interaction with other medicinal products and other forms of interaction).
Intolerance
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicinal product.
4.5 Interaction with other medicinal products and other forms of interaction
* Interactions
Hepatic enzyme inducers
Drugs which induce hepatic enzymes (especially cytochrome P450 3A4) increase the metabolism of contraceptive steroids and hence may result in breakthrough bleeding and pregnancy. The following have been shown to have
clinically important interactions with COCs and oestrogen/progestogen combinations like Co-cyprindiol:
Antiretroviral agents
• ritonavir;
• nelfinavir;
• nevirapine.
Anticonvulsants
• barbiturates (including phenobarbitone);
• primidone;
• phenytoin;-
• carbamazepine;
• oxcarbazepine;
• felbamate;
• topiramate.
Antibiotics/antifungals
• griseofulvin;
• rifampacin.
Herbal remedies
• St John's wort (Hypericum perforatum)
Managing the interactions with hepatic enzyme inducers
Since interactions of enzyme inducers, including the antibiotics rafampicin and griseofulvin, with oral contraceptives may lead to breakthrough bleeding and/or contraceptive failure the following precautions are recommended:
Women on short term treatment with any of these drugs should temporarily use a barrier method in addition to the COC or choose another method of contraception. With microsomal enzyme-inducing drugs, such as rifampicin and griseofulvin, the barrier method should be used during the time of concomitant drug administration and for 28 days after their discontinuation.
For women receiving long-term therapy with hepatic enzyme inducers, another method of contraception should be used.
Non-enzyme inducing antibiotics
Some clinical reports suggest that enterohepatic circulation of oestrogens may decrease when certain antibiotic agents are given, which may reduce ethinylestradiol concentrations (e.g. penicillins, tetracyclines).
Managing interactions with non-enzyme inducing antibiotics
Since interactions of some antibiotics with oral contraceptives may lead to breakthrough bleeding and/or contraceptive failure the following precautions are recommended:
Women on short term treatment with antibiotics (except rifampicin and griseofulvin) should temporarily use a barrier method in addition to the COC or choose another method of contraception. If the barrier method is chosen it should be used until 7 days after discontinuation of the antibiotics. 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 resuming with the next pack.
When drugs such as oral tetracyclines are being taken it is advisable to use additional non-hormonal methods of contraception (except the rhythm or temperature methods) since an extremely high degree of protection must be provided when Co-cyprindiol is being taken.
Effects on other drugs
Oral contraceptives and oestrogen/progestogen combinations like Co-cyprindiol 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.
Fertility, pregnancy and lactation
4.6
Co-cyprindiol is not indicated during pregnancy. If pregnancy occurs during treatment with Co-cyprindiol, further intake must be stopped.
Although low dose exposure to cyproterone acetate during pregnancy has not been associated with teratogenic effects or malformations, clinical data on fetal outcomes following exposure to cyproterone acetate is limited.
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 Co-cyprindiol 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 Co-cyprindiol, and must be excluded before such treatment is begun (see section 5.3 Preclinical safety data).
The use of Co-cyprindiol 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 breastfeeding should be advised not to take Co-cyprindiol 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. No effects on ability to drive and use machines have been observed in users of Co-cyprindiol.
4.8 Undesirable Effects
There is an increased risk of venous thromboembolism for all women who use Co-cyprindiol. For more information see Section 4.4 Special warnings and precautions for use.
Undesirable-effects which have been seen in connection with the use of combined oral contraceptive pills have also been experienced when taking Co-cyprindiol tablets. In rare cases tenderness in the breasts, gastric upsets, nausea, vomiting, headaches, changes in body weight, 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.
In predisposed women, use of Co-cyprindiol can sometimes cause chloasma which is exacerbated by exposure to sunlight. Such women should avoid prolonged exposure to sunlight.
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.
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 occur during tablet-taking, especially in the first few cycles and normally cease spontaneously. Co-cyprindiol should therefore, be continued even if irregular bleeding occurs. If irregular bleeding is persistent, appropriate diagnostic measures to exclude 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 Co-cyprindiol.
The use of combined oral contraceptives (COCs) is associated with an increased risk for venous (deep venous thrombosis, pulmonary embolism) and arterial (myocardial infarction, transient ischaemic attack) thromboembolism (See Section 4.4. Special warnings and precautions for use).
Effect on blood chemistry:
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.
Transient liver function changes may occur; occasionally there may also be raised blood-pressure in women who are predisposed to this.
The radio-iodine uptake shows that thyroid function is unchanged. There is a rise in serum protein-bound iodine, similar to that in pregnancy and during the administration of oestrogens. This is due to the increased capacity of the plasma proteins for binding thyroid hormones, rather than to any change in glandular function. In women taking the medicinal product, the content of protein-bound iodine in blood serum should, therefore, not be used for the evaluation of thyroid function.
The medicinal product may accelerate erythrocyte sedimentation in the absence of any disease. This effect is due to change in the proportion of the plasma protein fractions. Increases in plasma copper, iron and alkaline phosphatase have also been recorded.
Refer to Section 4.4. "Special warnings and special precautions for use" for additional information.
4.9 Overdose
There are no specific antidotes and treatment should be symptomatic.
Symptoms of overdose are nausea, vomiting and, in females, withdrawal bleeding.
5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic properties
Pharmacotherapeutic group: Antiandrogens and Estrogens; Cyproterone and oestrogen
ATC code: G03HB01
Cyproterone acetate possesses anti-androgenic and progestational activity. It blocks androgen-receptors; it also reduces androgen synthesis by a negative feedback effect on the hypothalamo-pituitary-ovarian systems. Sex hormonebinding globulin (SHBG) levels are increased by the oestrogen component of the medicinal product, thus reducing the free, circulating plasma levels of androgens. Unlike some other progestogens, cyproterone acetate has no tendency to reduce SHBG levels. The oestrogen component also acts as an oral contraceptive, with a mode of action similar to those for oestrogens in general.
The results from epidemiological investigations have shown that the use of high dosed combined oral contraceptives (50^g ethinylestradiol) lowers the risk of endometrial and ovarian cancer. However, it has yet to be established whether the beneficial effects also apply to the lower dose oral contraceptives.
5.2. Pharmacokinetic properties
Cyproterone Acetate
After oral administration of 2mg Cyproterone Acetate sugar-coated tablets, CPA is completely absorbed. It is rapidly metabolised and slowly excreted in the faeces and urine. Its terminal t/ after a single oral 50mg dose to healthy volunteers has been reported to be between 38h (radioimmunoassay) and 39h (total radioactivity) although a terminal half-life in healthy volunteers of up to a 100 hours has also been reported.
Cyproterone Acetate is metabolized (by cytochrome P450 3A4) first by hydrolysis to free cyproterone, then by 15 P-hydroxylation to 15-hydroxycyproterone. This metabolite has 10% of the progestational activity of Cyproterone Acetate but has similar anti-androgenic activity. Excretion is effected slowly via the kidneys and faeces.
Ethinylestradiol is rapidly and almost completely absorbed from the gastrointestinal tract, but is to a certain degree subject to a first-past metabolism in the intestine wall. Bioavailability amounts to approximately 40%. Maximum plasma concentrations are achieved 1-2 hours after oral application. Ethinylestradiol accumulates in the body fat and endometrium. The reported (half-life P/2) varies from 6 to 30 hours. In comparison to other oestrogens it is only metabolised slowly in the liver. It is conjugated with glucuronic acid and sulphate. Ethinylestradiol is subject to a clear enterohepatic cycle. 60% of excretion is effected via the kidneys and 40% via faeces.
5.3 Preclinical safety data
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 Co-cyprindiol.
Genotoxicity and carcinogenicity
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 Co-cyprindiol in humans if used in accordance with the directions for the given indication and at the recommended dose.
6. PHARMACEUTICAL PARTICULARS
6.1. List of excipients
Tablet core:
Lactose monohydrate Maize Starch Povidone Talc
Magnesium Stearate (E572)
Coating:
Saccharose
Calcium Carbonate (E170)
Talc
Titanium Dioxide (E171)
Povidone Macrogol Glycerol 85%
Iron Oxide yellow (E172)
Montan Glycol Wax
6.2. Incompatibilities
Not applicable
6.3. Shelf Life
3 years
6.4. Special precautions for storage
Store in the original package.
6.5. Nature and contents of container
Blister strips PVC/aluminium blister PVC/PVDC/aluminium blister
Pack size 21, 1 x 21 tablets 63, 3 x 21 tablets 126, 6 x 21 tablets
6.6. Instructions for use and handling
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Sandoz Limited
Frimley Business Park
Frimley
Camberley
Surrey
GU16 7SR
United Kingdom
8. MARKETING AUTHORISATION NUMBER(S)
PL 04416/0465
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
05/01/09
06/01/2015