CYCLO-PROGYNOVA 2 MG - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Cyclo-Progynova® 2mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

White Tablets

Pale Brown Tablets

2mg oestradiol valerate

500 micrograms norgestrel

2mg oestradiol valerate

Sugar-coated tablets.

4.1 Therapeutic indications

Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in perimenopausal and postmenopausal wo­men.

Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis. (See Section 4.4 Special warnings & precautions for use).

4.2 Posology and method of administration

Cyclo-Progynova is a cyclic HRT product. One tablet is to be taken orally once a day for 21 days, followed by a 7 day tablet free interval. Therefore each new pack is started after a 28 day cycle. The white tablets should be taken from days 1 to 11 followed by the brown tablets from days 12 to 21. It is recommended that the tablets are taken at the same time every day.

For initiation and continuation of treatment of peri- and post-menopausal symptoms the lowest effective dose for the shortest duration (see also Section 4.4) should be used. For the prevention of osteoporosis Cyclo-Progynova 2mg should be used.

For women still having periods, the first tablet should be taken on the 5th day of their menstrual period. If menstruation has stopped, or is infrequent or sporadic, then the first tablet can be taken any time.

If the patient is being transferred from a continuous HRT product, the patient may start Cyclo-Progynova on any convenient day. For those transferring from a cyclic or sequential product, Cyclo-Progynova should be started following completion of the previous regimen.

If a tablet is missed, it should be taken as soon as possible, unless it is more than 12 hours late. In this case the missed tablet should be left in the pack and the next tablet taken at the right time. Missing a dose may result in breakthrough bleeding or spotting.

Unless there is a previous diagnosis of endometriosis, it is not recommended that progestagen-containing HRT be given to hysterectomised wo­men.

Cyclo-Progynova is not indicated for use in children and adolescents.

There are no data suggesting a need for dosage adjustment in women aged 65 years or older (see section 4.4 Special warnings and precautions for use).

Cyclo-Progynova has not been specifically studied in patients with hepatic impairment. (see 4.3 Contraindi­cations).

Cyclo-Progynova has not been specifically studied in renally impaired patients. Available data do not suggest a need for dosage adjustment in this patient population.

4.3 Contraindications

– Known, past or suspected breast cancer;

– Known or suspected oestrogen-dependent malignant tumours (e.g. endometrial cancer);

– Undiagnosed genital bleeding;

– Untreated endometrial hyperplasia;

– Previous or current venous thromboembolism (deep venous thrombosis, pulmonary embolism)

– Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency, see section 4.4);

– Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction);

– Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal;

– Known hypersensitivity to the active substances or to any of the excipients;

– Porphyria.

4.4 Special warnings and precautions for use

For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.

Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited.

Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women.

Medical Examination/Follow-up:

Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications (section 4.3) and warnings for use (section 4.4). During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see ‘Breast cancer’ below).

Investigations, including appropriate imaging tools, e.g. mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.

Conditions that need supervision

If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely monitored. It should be taken into account that these conditions may recur or may be aggravated during treatment with Cyclo-Progynova 2mg, in particular:

– Leiomyoma (uterine fibroids) or endometriosis

– Risk factors for thromboembolic disorders (see below)

– Risk factors for oestrogen dependent tumours, e.g. 1st degree heredity for breast cancer

– Hypertension

– Liver disorders (e.g. Liver adenoma)

– Diabetes mellitus with or without vascular involvement

– Cholelithiasis

– Migraine or severe headache

– Systemic lupus erythematosus

– A history of endometrial hyperplasia (see below)

– Epilepsy

– Asthma

– Otosclerosis

Close medical supervision (including periodic measurement of prolactin levels) is necessary if the patient suffers from prolactinoma.

Reasons for immediate withdrawal of therapy

Therapy should be discontinued in case a contra-indication is discovered and in the following situations:

– Significant increase in blood pressure

– Pregnancy

– Jaundice or deterioration in liver function.

– New onset of migraine-type headache

Endometrial hyperplasia and carcinoma

In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among oestrogen-only users varies from 2-to 12-fold greater compared with non-users, depending on the duration of treatment and oestrogen dose (see section 4.8). After stopping treatment risk may remain elevated for at least 10 years.

The addition of a progestagen cyclically for at least 12 days per month/28 day cycle or continuous combined oestrogen-progestagen therapy in non-hysterectomised women prevents the excess risk associated with oestrogen-only HRT.

Break-through bleeding and spotting may occur during the first months of treatment. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include an endometrial biopsy to exclude endometrial malignancy.

Breast cancer

The overall evidence shows an increased risk of breast cancer in women taking combined oestrogen-progestagen or oestrogen-only HRT, that is dependent on the duration of taking HRT.

Combined oestrogen-progestagen therapy

The randomised placebo-controlled trial the (Women’s Health Initiative study (WHI), and a meta-analysis of prospective epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined oestrogen-progestagen for HRT that becomes apparent after about 3 (1–4) years (see section 4.8).

Oestrogen-only therapy

The WHI trial found no increase in the risk of breast cancer in hysterectomised women using oestrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is lower than that found in users of oestrogen-progestagen combinations (see section 4.8).

Results from a large meta-analysis showed that after stopping treatment, the excess risk will decrease with time and the time needed to return to baseline depends on the duration of prior HRT use. When HRT was taken for more than 5 years, the risk may persist for 10 years or more.

HRT, especially oestrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Ovarian cancer

Ovarian cancer is much rarer than breast cancer.

Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking oestrogen-only or combined oestrogen-progestagen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping.

Some other studies, including the WHI trial, suggest that use of combined HRTs may be associated with a similar, or slightly smaller, risk (see section 4.8).

Venous Thromboembolism

HRT is associated with a 1.3–3 fold risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT than later (section 4.8).

Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients (see section 4.3).

Generally recognised risk factors for VTE include, use of oestrogens, older age, major surgery, prolonged immobilisation, obesity (BMI >30kg/m2), pregnancy/pos­tpartum period, systemic lupus erythematosus (SLE), and cancer.

There is no consensus about the possible role of varicose veins in VTE.

As in all postoperative patients, prophylactic measures need to be considered to prevent VTE following surgery. If prolonged immobilisation is to follow elective surgery temporarily stopping HRT 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilised.

In women with no personal history of VTE but with a first degree relative with a history of thrombosis at a young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening).

If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is ‘severe’ (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT is contraindicated.

Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT

If VTE develops after initiating therapy the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of leg, sudden pain in chest, dyspnoea)

Coronary Arterial Disease (CAD)

There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined oestrogen-progestagen or oestrogen only HRT.

Combined oestrogen-progestagen therapy

The relative risk of CAD during use of combined oestrogen+pro­gestagen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to oestrogen+pro­gestagen use is very low in healthy women close to menopause, but will rise with more advanced age.

Oestrogen-only therapy

Randomised controlled data found no increased risk of CAD in hysterectomised women using oestrogen-only therapy.

Ischaemic Stroke

Combined oestrogen-progestagen and oestrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see section 4.8).

Other Conditions

Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed since it is expected that the level of circulating active ingredients of Cyclo-Progynova may increase.

Women with pre-existing hypertriglyce­ridemia should be followed closely during oestrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.

Oestrogens increase thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay), or T3 levels (by radio-immunoassay). T3 resin uptake is decreased reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensino­gen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).

HRT use does not improve cognitive function. There is some evidence of increased risk of probable dementia in women who start using continuous combined or oestrogen-only HRT after the age of 65.

Lactose

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

Sucrose

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction The metabolism of oestrogens and progestagens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine), and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones. Herbal preparations containing St John's Wort (Hypericum Perforatum) may induce the metabolism of oestrogens and progestagens.

Clinically, an increased metabolism of oestrogens and progestagens may lead to decreased efficacy and changes in uterine bleeding profile

The requirement for oral antidiabetics or insulin can change.

4.6 Fertility, Pregnancy and lactation

Cyclo-Progynova is not indicated during pregnancy or lactation.

If pregnancy occurs during medication with Cyclo-Progynova treatment should be withdrawn immediately. No data on exposed pregnancies are available. Studies in animals have not shown reproductive toxicity.

The results of most epidemiological studies to-date, relevant to inadvertent foetal exposure to combinations of oestrogens and progestagens indicate no teratogenic or foetotoxic effect.

4.7 Effects on ability to drive and use machines None known.

4.8 Undesirable effects

During the first few months treatment, breakthrough bleeding, spotting and breast tenderness or enlargement can occur. These are usually temporary and normally disappear after continued treatment.

The most appropriate MedDRA term (version 8.0) to describe a certain reaction is listed.

Synonyms or related conditions are not listed, but should be taken into account as well.

In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema (see section 4.4 Special Warnings and special precautions for use).

Other reactions have also been reported in association with oestrogen/pro­gestagen treatment:

– Oestrogen-dependent neoplasms benign and malignant, e.g. breast (see below) and endometrial (see below) cancer

– Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone replacement therapy users than among non-users. For further information, see section 4.3 Contraindi­cations and 4.4 Special warnings and precautions for use

– Myocardial infarction and stroke

– Gall bladder disease

– Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura

– Probable dementia (see Section 4.4)

– In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.

Breast cancer risk

An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestagen therapy for more than 5 years.

The increased risk in users of oestrogen-only therapy is lower than that seen in users of oestrogen-progestagen combinations.

The level of risk is dependent on the duration of use (see section 4.4).

Absolute risk estimations based on results of the largest randomised placebo-controlled trial (WHI-study) and the largest meta-analysis of prospective epidemiological studies are presented.

Largest meta-analysis of prospective epidemiological studies

Estimated additional risk of breast cancer after 5 years’ use in women with BMI 27 (kg/m2)

Taken from baseline incidence rates in England in 2015 in women with BMI 27 (kg/m2)

Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately.

Taken from baseline incidence rates in England in 2015 in women with BMI 27 (kg/m2)

Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately.

US WHI studies – additional risk of breast cancer after 5 years’ use

WHI study in women with no uterus, which did not show an increase in risk of breast cancer.

JWhen the analysis was restricted to women who had not used HRT prior to the study there was no increased risk apparent during the first 5 years of treatment: after 5 years the risk was higher than in non-users.

Endometrial cancer risk

Postmenopausal women with a uterus

The endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT.

In women with a uterus, use of oestrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4). Depending on the duration of oestrogen-only use and oestrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 women between the ages of 50 and 65.

Adding a progestagen to oestrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study the use of five years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer (RR of 1.0 (0.8–1.2)).

Ovarian Cancer

Use of oestrogen-only or combined oestrogen-progestagen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed (see Section 4.4.)

A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.31–1.56). For women aged 50 to 54 years taking 5 years of HRT, this results in about 1 extra case per 2000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer of a 5-year period.

Risk of venous thromboembolism

HRT is associated with a 1.3–3-fold increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of using HT (see section 4.4). Results of the WHI studies are presented:

WHI Studies – Additional risk of VTE over 5 years’ use

* Study in women with no uterus.

Risk of coronary artery disease

The risk of coronary artery disease is slightly increased in users of combined oestrogen-progestagen HRT over the age of 60 (see section 4.4).

Risk of ischaemic stroke

The use of oestrogen-only and oestrogen + progestagen therapy is associated with an up to 1.5 fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT.

This relative risk is not dependent on age or on duration of use, but as the baseline risk is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age, see section 4.4.

WHI studies combined – Additional risk of ischaemic stroke* over 5 years’ use

*no differentiation was made between ischaemic and haemorrhagic stroke.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Overdose may cause nausea and vomiting, and withdrawal bleeding may occur in some women. There are no specific antidotes, and therefore treatment should be symptomatic.

5.1 Pharmacodynamic properties

The estrogen in Cyclo-Progynova is estradiol valerate, a prodrug of the natural human 17Bestradiol. Synthetic 17 P-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms.

Oestrogens prevent bone loss following menopause or Ovariectomy.

The constituent norgestrel is a synthetic progestogen.

As oestrogens promote the growth of the endometrium, unopposed oestrogen increase the risk of endometrial hyperplasia and cancer. The addition of a progestagen greatly reduces the oestrogen induced risk of endometrial hyperplasia in non-hysterectomised wo­men.

With the composition and the sequential regimen of Cyclo-Progynova, including an estrogen monophase for 11 days, an estrogen-progestogen combination for 10 days and a treatment-free interval of 7 days, a menstrual cycle is established in women with an intact uterus, provided the preparation is taken regularly.

Hormone replacement therapy (HRT) alleviates many of the symptoms of estradiol deficiency in menopausal woman such as hot flushes, excessive sweating, urogenital atrophy with symptoms of vaginal dryness and dyspareunia.

Relief of menopausal symptoms was achieved by the third cycle after initiation of treatment. In a clinical trial 314 subjects were enrolled and treated with 2 mg EV/0.5 mg NG, 235 subjects completed the study. 93.3% of the subjects who completed showed a reduction of the mean number of hot flushes per week of at least 50% after 3 cycles of treatment. 61.1% of subjects had no hot flushes any more at cycle 3. In another clinical trial one third of the subjects was free of vasomotor symptoms after one treatment cycle.

The Kupperman Index, related to the most common menopausal complaints which are weighted according to their importance, significantly decreased from baseline at cycle 3.

Data from clinical trials indicate that regular monthly withdrawal bleeding occurred in approximately 90% of women. The mean duration of withdrawal bleeding was 3.8 days. Withdrawal bleeding starts on average 3.1 days after the last pill of the progestagen phase. The amenorrhea rate (no bleeding or spotting) is less than 5%.

Oestrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass.

The effect of oestrogens on the bone mineral density is dose-dependent.

Protection appears to be effective for as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated women.

Evidence from the WHI trial and meta-analysed trials shows that current use of HRT, alone or in combination with a progestagen – given to predominantly healthy women – reduces the risk of hip, vertebral, and other osteoporotic fractures. HRT may also prevent fractures in women with low bone density and/or established osteoporosis, but the evidence for that is limited.

5.2 Pharmacokinetic propertiesEstradiol valerate

Absorption

Estradiol valerate is rapidly and completely absorbed. The steroid ester is cleaved into estradiol and valeric acid during absorption and the first liver passage. At the same time, estradiol undergoes metabolism into estrone, estriol and estrone sulfate. Only about 3 % of estradiol becomes bioavailable after oral administration of estradiol valerate. Food does not affect the bioavailability of estradiol.

Distribution

Following single oral administration of 4mg estradiol valerate, maximum concentrations of estradiol in serum of approximately 50–60pg/ml (25–30pg/ml when corrected for a dose of 2mg) are generally reached between 4–9 hours after tablet intake. Estradiol binds to albumin and the sex hormone binding globulin (SHBG). However, the binding to SHBG is lower than that of levonorgestrel. The unbound fraction of estradiol in serum is about 1–1.5 % and the SHBG-bound fraction is in the range of 30–40 %.

The apparent volume of distribution of estradiol after single intravenous administration is about 1 l/kg.

Metabolism

After the ester cleavage of the exogenously administered estradiol valerate, the metabolism of the drug follows the biotransformation pathways of endogenous estradiol. Estradiol is mainly metabolized in the liver but also extrahepatically e.g. in gut, kidney, skeletal muscles and target organs. These processes involve the formation of estrone, estriol, catecholestrogens and sulfate and glucuronide conjugates of these compounds, which are all distinctly less estrogenic or even nonestrogenic.

Elimination

The total serum clearance of estradiol following single intravenous administration, shows high variability in the range of 10–30 ml/min/kg. A certain proportion of estradiol metabolites are excreted in the bile and undergo a so-called enterohepatic circulation. Ultimately estradiol metabolites are mainly excreted as sulfates and glucuronides with the urine.

Steady state conditions

In relation to the single dose, approximately two times higher serum levels of estradiol are observed after multiple administration. On average, the concentration of estradiol varies between 30 (minimum levels) and 60 pg/ml (maximum levels). Estrone, as a less estrogenic metabolite, reaches about 8-times higher concentrations in serum, estrone sulfate reaches approximately 150-times higher concentrations. After stopping the treatment with CycloProgynova, pre-treatment levels of estradiol and estrone are reached within 2–3 days. No distinct difference in the estrogen levels is observed between the treatment phase with estradiol valerate alone or in combination with norgestrel.

Absorption

After oral administration, norgestrel is absorbed rapidly and completely. The active component of the racemate norgestrel is levonorgestrel which becomes completely bioavailable from the racemate and accounts for about half of the dose of norgestrel.

Distribution

On an average, maximum concentrations of levonorgestrel in serum of 7–8 ng/ml are already reached within 1–1.5 hours after a single administration of Cyclo Progynova. Subsequently, serum levels of levonorgestrel decline biphasically with a mean terminal half-life of 27 hours and reach minimum concentrations of about 1 ng/ml 24 hours post dose.

Levonorgestrel binds to albumin and SHBG. Only about 1–1.5 % of the total levonorgestrel concentration in serum is not protein-bound. The relative fractions of free, albumin- and SHBGbound levonorgestrel are strongly dependent on the concentration of SHBG in serum. After induction of the binding proteins, the fraction bound to SHBG increases whereas the unbound fraction and that bound to albumin decreases. At the end of the estrogen monophase of the Cyclo-Progynova treatment cycle, the concentration of SHBG reaches the highest levels in serum which then decreases to the lowest levels at the end of the combination phase. Accordingly, the free fraction of levonorgestrel amounts to about 1 % at the beginning and about 1.5 % at the end of the combination phase. The corresponding fractions of levonorgestrel bound to SHBG are 70 and 65 %, respectively.

Biotransformation

Norgestrel is completely metabolized. Biotransformation of the active substance levonorgestrel follows the known pathways of steroid metabolism. Pharmacologically active metabolites are not known.

Elimination

The total clearance rate of levonorgestrel from serum is 1 ml/min/kg. With a half-life of about 1 day, approximately the same proportions of the metabolites of norgestrel are excreted with the urine and the bile.

Steady-state conditions

Based on the elimination half-life of levonorgestrel in serum of about 24 hours, an accumulation of the active substance in serum would be expected. Accordingly, elevated trough levels of about 1 ng/ml are observable after repeated administration. However, due to the simultaneous change in the protein binding capacity during treatment (decrease in SHBG concentration), the area under the serum levels-time course of levonorgestrel does not really differ between the beginning and the end of the 10-day treatment phase with the estrogen/proges­togen combination. Thus, no accumulation of levonorgestrel in serum is observed after multiple administration of Cyclo-Progynova.

5.3 Preclinical safety data

There are no preclinical safety data which could be of relevance to the prescriber and which is 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 [E572], sucrose, calcium carbonate [E170], polyethylene glycol 6000, montan glycol wax, titanium dioxide [E171], yellow ferric oxide [E172], red brown ferric oxide [E172], glycerin.

6.2 Incompatibilities

None known.

6.3 Shelf life

5 years.

6.4 Special precautions for storage Not applicable.

6.5 Nature and contents of container

Cardboard outer containing either: one rectangular blister pack or three rectangular blister packs. Each pack consists of aluminium foil and PVC and contains 21 tablets.

6.6 Special precautions for disposal

No special requirements for disposal

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

7 MARKETING AUTHORISATION HOLDER

Mylan Products Ltd.,

Station Close,

Potters Bar,

Hertfordshire,

EN6 1TL, UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 46302/0157

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

01/01/2010