ACNOCIN 2000/35 TABLETS - summary of medicine characteristics

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 2 mg of cyproterone acetate and 0.035 mg of ethinylestradiol.

Excipient(s) with known effect:

Each coated tablet contains 27.659 mg lactose (as monohydrate) and 19.637 mg sucrose.

For the 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 therefore not 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.

Posology

No previous hormonal contraception (during the preceding month):

First treatment course: Tablets should be started on day 1 of the natural menstrual cycle (first day of bleeding), one tablet daily for 21 days. Tablettaking 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.

Subsequent courses: Each subsequent course is started after 7 tablet-free days have followed the preceding course.

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 dose. 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 the usual time. In addition, a supplemental non-hormonal contraceptive method should be used for the next 7 days.

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).

Children and adolescents

Co-cyprindiol is only indicated after menarche.

Elderly

Not applicable. Co-cyprindiol is not indicated after menopause.

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 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.

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 active substances or any of the excipients listed in section 6.1

Concomitant use with another hormonal contraceptive (see section 4.1)

Venous thrombosis present or in history (deep venous thrombosis, pulmonary embolism)

Arterial thrombosis present or in history (e.g. myocardial infarction) or prodromal conditions (e.g. angina pectoris and transient ischaemic attack)

Presence or history of cerebrovascular accident

The presence of a severe or multiple risk factor(s) for venous or arterial thrombosis (see section 4.4) such as:

– diabetes mellitus with vascular symptoms

– severe hypertension

– severe dyslipoproteinaemia

Hereditary or acquired predisposition for venous or arterial thrombosis, such as activated protein C (APC) resistance, antithrombin-III-deficiency, protein C deficiency, protein S deficiency, hyperhomocyste­inaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant)

Known or suspected pregnancy (see section 4.6).

Breast-feeding (see section 4.6).

Abnormal vaginal bleeding of unknown cause

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

Co-cyprindiol is contraindicated for concomitant use with the medicinal products containing ombitasvir/pa­ritaprevir/ri­tonavir and dasabuvir, (see sections 4.4 and section 4.5).

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)

Meningioma or history of meningioma

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.

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 94 mmHg (see also Section 4.4)

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 Co-cyprindiol.

Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use (see section 4.8). Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their physician in case of mood changes and depressive symptoms, including shortly after initiating the treatment.

When stopping oral contraception non-hormonal contraception should be used to ensure contraceptive protection is maintained, if needed.

1. Occurrence for the first time, or exacerbation, of migrainous headaches or unusually frequent or unusually severe headaches.

2. Sudden disturbances of vision or hearing or other perceptual disorders.

3. First signs of thrombosis or blood clots (e.g. unusual pains in or swelling of the leg(s), stabbing pains on breathing or coughing for no apparent reason). Feeling of pain and tightness in the chest.

4. Six weeks before an elective major operation (e.g. abdominal, orthopaedic), any surgery to the legs, medical treatment for varicose veins or prolonged immobilisation, e.g. after accidents or surgery. Do not restart until 2 weeks after full ambulation. In case of emergency surgery, thrombotic prophylaxis is usually indicated e.g. subcutaneous heparin.

5. Onset of jaundice, hepatitis, itching of the whole body.

6. Significant rise in blood pressure

7. Onset of severe depression.

8. Severe upper abdominal pain or liver enlargement.

9. Clear worsening of conditions known to deteriorate during use of hormonal contraception or during pregnancy (see section 4.4).

10. Pregnancy is a reason for stopping immediately (see section 4.6)

11. Meningioma:

The occurrence of meningiomas (single and multiple) has been reported in association with use of cyproterone acetate, especially at high doses of 25 mg and above and for prolonged time (see section 5.1). If a patient is diagnosed with meningioma, any cyproterone containing treatment, including Co-cyprindiol, must be stopped, as a precautionary measure.

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 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

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)

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, haemolytic uraemic syndrome, chronic inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis) and sickle cell disease.

The increased risk of thromboembolism in the puerperium must be considered (for information on ‘Pregnancy and lactation’ see section 4.6).

An increase in frequency or severity of migraine during use of Cyproterone acetate/ethiny­lestradiol (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 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.

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.

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 Cyproterone acetate/ethiny­lestradiol.

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). Although small increases in blood pressure have been reported in many women taking COCs or Co-cyprindiol, clinically relevant increases are rare. However, if a sustained clinically significant hypertension develops during the use of a COC then it is prudent for the physician to withdraw the COC and treat the hypertension. Where considered appropriate, COC use may be resumed if normotensive values can be achieved with antihypertensive therapy.

Conditions which deteriorate with pregnancy or during previous COC or 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 Cyproterone acetate/ethiny­lestradiol, 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

Epilepsy

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.

ALT elevations

During clinical trials with patients treated for hepatitis C virus infections (HCV) with the medicinal products containing ombitasvir/pa­ritaprevir/ri­tonavir and dasabuvir with or without ribavirin, transaminase (ALT) elevations higher than 5 times the upper limit of normal

(ULN) occurred significantly more frequent in women using ethinylestradiol-containing medications such as combined hormonal contraceptives (CHCs) (see sections 4.3 and 4.5).

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).

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 Cyproterone acetate/ethiny­lestradiol 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), gastro-intestinal disturbances (see section 4.2) during tablet taking or concomitant medication (see section 4.5).

Intolerance

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Patients with rare hereditary problems of fructose intolerance, glucosegalactose malabsorption or sucrase-isomaltase insufficiency should not take this medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.

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.

Enzyme induction can already be observed after a few days of treatment. Maximal enzyme induction is generally seen within a few weeks. After the cessation of medicinal product therapy enzyme induction may be sustained for about 4 weeks.

Women on short treatment with any of these drugs 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 the concomitant medicinal product administration and for 28 days after its discontinuation. If the period during which the barrier method is used runs beyond the end of the 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 tabletfree 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 treatment with enzyme-inducers, another method of contraception should be used.

The following have been shown to have clinically important interactions with Co-cyprindiol:

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.

Substances decreasing the clearance of CHC (enzyme inhibitors)

The clinical relevance of potential interactions with enzyme inhibitors remains unknown.

Concomitant administration of strong CYP3A4 inhibitors can increase plasma concentrations of the oestrogen or the progestin or both.

Etoricoxib doses of 60 to 120 mg/day have been shown to increase plasma concentrations of ethinylestradiol 1.4 to 1.6-fold, respectively when taken concomitantly with a combined hormonal contraceptive containing 0.035 mg ethinylestradiol.

Effects on other medicinal products

Oral contraceptives and oestrogen/pro­gestogen combinations like Co-cyprindiol may affect the metabolism of certain other active substances. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporin) or decrease (e.g. lamotrigine).

Clinical data suggest that ethinylestradiol is inhibiting the clearance of CYP1A2 substrates leading to a weak (e.g. theophylline) or moderate (e.g. tizanidine) increase in their plasma concentration.

Pharmacodynamic interactions

Concomitant use with the medicinal products containing ombitasvir/pa­ritaprevir/ri­tonavir and dasabuvir, with or without ribavirin may increase the risk of ALT elevations (see sections 4.3 and 4.4). Therefore, Co-cyprindiol -users must switch to an alternative method of contraception (e.g., progestagen-only contraception or non-hormonal methods) prior to starting therapy with this combination drug regimen. Co-cyprindiol can be restarted

2 weeks following completion of treatment with this combination drug regimen.

Other forms of interactions

Laboratory tests

The use of oral contraceptives may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of carrier proteins and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Laboratory staff should therefore be informed about oral contraceptive use when laboratory tests are requested.

4.6 Fertility, pregnancy and lactation

Pregnancy

Co-cyprindiol is not indicated during pregnancy. If pregnancy occurs during treatment with Co-cyprindiol, 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 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).

Breast-feeding

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

Summary of the safety profile

The most commonly reported adverse reactions with Co-cyprindiol are nausea, abdominal pain, increased weight, headache, depressed mood, altered mood, breast pain, breast tenderness. They occur in > 1 % of the users.

There is an increased risk of thromboembolism for all women who use cyproterone acetate/ethiny­lestradiol (see section 4.4).

Description of selected adverse reactions

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.

An increased risk of arterial and venous thrombotic and thromboembolic events, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis and pulmonary embolism has been observed in women using CHCs, which are discussed in more detail in section 4.4.

The following serious adverse events have been reported in women using cyproterone acetate/ethiny­lestradiol, which are discussed in section 4.4:

Venous thromboembolic disorders

Arterial thromboembolic disorders

Hypertension

Liver tumours (benign and malignant)

Occurrence or deterioration of conditions for which association with COC use is not conclusive: 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; haemolytic uremic syndrome; Sydenham's chorea; epilepsy

Chloasma

Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal

In women with hereditary angioedema exogenous oestrogens may induce or exacerbate symptoms of angioedema

The frequency of diagnosis of breast cancer is very slightly increased among OC users. As breast cancer is rare in women under 40 years of age the excess number is small in relation to the overall risk of breast cancer. Causation with COC or cyproterone acetate/ethiny­lestradiol use is unknown. For further information, see sections 4.3 and 4.4.

Changes in glucose tolerance or effect on peripheral insulin resistance have been reported in women using COCs or cyproterone acetate/ethiny­lestradiol (see section 4.4).

Interactions

Breakthrough bleeding and/or contraceptive failure may result from interactions of other medicinal products (enzyme inducers) with oral contraceptives (see section 4.5).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme:

www.mhra.gov.uk/y­ellowcard or search for MHRA Yellow Card in Google play or Apple App store.

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 estrogen

ATC code: G03HB01

Cyproterone acetate/ethiny­lestradiol blocks androgen-receptors. It also reduces androgen synthesis both by negative feedback effect on the hypothalamo-pituitiary-ovarian systems and by the inhibition of androgen-synthesising enzymes.

Although Cyproterone acetate/ethiny­lestradiol also acts as an oral contraceptive, it is not recommended in women solely for contraception, but should be reserved for those women requiring treatment for the androgendependent skin conditions described.

Based on results from a French epidemiological cohort study, a cumulative dose-dependent association between cyproterone acetate and meningioma has been observed. This study was based on data from the French Health Insurance (CNAM) and included a population of 253,777 women using 50 –100 mg cyproterone tablets. The incidence of meningioma treated with surgery or radiotherapy was compared between women exposed to high-dose cyproterone acetate (cumulative dose >3 g) and women who were slightly exposed to cyproterone acetate (cumulative dose <3 g). A cumulative doseresponse relationship was demonstrated.#

a Adjusted based on age as a time-dependent variable and oestrogen at inclusion

A cumulative dose of 12g for example can correspond with one year of treatment with 50 mg/day for 20 days each month.

5.2 Pharmacokinetic properties

Cyproterone acetate

Absorption

Following oral administration of 2mg Cyproterone acetate (CPA) sugar-coated tablets, CPA is completely absorbed in a wide dose range.

The ingestion of Co-cyprindiol effects a maximum serum level of 15ng cyproterone acetate/ml at 1.6 hours.

Distribution

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.

Biotransformation

Cyproterone acetate is metabolised by various pathways including hydroxylations and conjugations. The main metabolite in human plasma is the 153-hydroxy derivative.

Elimination

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 15ng/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 Co-cyprindiol was 109% when compared to an aqueous microcrystalline suspension.

Ethinylestradiol

Absorption

Orally administered ethinylestradiol is rapidly and completely absorbed. Following ingestion of Co-cyprindiol maximum drug serum levels of about 80pg/ml are reached at 1.7 hours.

Distribution

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.

Biotransformation

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.

In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1 and CYP1A2 as well as a mechanism based inhibitor of CYP3A4/5, CYP2C8 and CYP2J2.

Elimination

Unchanged drug is not excreted. Ethinylestradiol metabolites are excreted at a urinary to biliary ratio of 4:6 with a half-life of about 1 day.

Steady-state conditions

According to the half-life of the terminal disposition phase from plasma and the daily ingestion steady state plasma levels are reached after 3 – 4 days and are higher by 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 the treatment with cyproterone acetate/ethiny­lestradiol SHBG concentrations in serum increased from about 100 nmol/l to 300 nmol/l and the serum concentrations of CBG were increased from about 50 |ig/ml to 95 |ig/ml.

5.3 Preclinical safety data

Systemic toxicity

Non-clinical 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 cyproterone acetate/ethiny­lestradiol 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 K25

Talc

Magnesium Stearate (E572)

Coating:

Sucrose

Calcium Carbonate (E170)

Talc

Titanium Dioxide (E171)

Povidone K90

Polyethylene glycole 6000

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 in order to protect from moisture.

6.5 Nature and contents of container

PVC/aluminium blister packs or PVC/PVDC/aluminium blister packs containing 21 (1×21), 63 (3×21) and 126 (6×21) coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.