1. Name Of The Medicinal Product
Cyclo-Progynova® 2mg.
2. Qualitative And Quantitative Composition
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3. Pharmaceutical Form
Sugar-coated tablets.
4. Clinical Particulars
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 & Special 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.
4.3 Contraindications
- known, past or suspected breast cancer
- known or suspected oestrogen-dependent malignant tumours (e.g. endometrial cancer)
- acute liver disease or a history of liver disease unless liver function tests have returned to normal
- undiagnosed genital bleeding
- untreated endometrial hyperplasia
- previous idiopathic or current venous thromboembolism (deep vein thrombosis, pulmonary embolism)
- active or recent arterial thomboembolic disease (e.g. angina, myocardial infarction)
- 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.
Medical Examination/Follow-up:
Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical examination (including pelvic and breast) 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 dependent on the clinical needs of the individual. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see 'breast cancer' below). Investigations, including mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.
Before starting treatment, pregnancy should be excluded. If withdrawal bleeding fails to occur at about 28-day intervals, the possibility of pregnancy should be considered in peri-menopausal women.
The patient may experience blood loss after completing each pack.
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
- a history of, or 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
- hereditary angioedema
Reasons for immediate withdrawal of therapy
Therapy should be immediately discontinued in the following situations:
- contraindications are discovered
- significant increase in blood pressure
- pregnancy
- jaundice or deterioration in liver function.
- migrainous headaches occur for the first time
Endometrial Hyperplasia
The risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods (see section 4.8). The addition of a progestagen for 10 days per cycle in non-hysterectomised women reduces, but does not eliminate, this risk.
Breakthrough bleeding and spotting may occur during the first few months of treatment, but if this occurs after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated. This may include an endometrial biopsy to exclude endometrial malignancy.
Breast Cancer
A randomised placebo-controlled trial, the Women's Health Initiative study (WHI), and epidemiological studies, including the Million Women Study (MWS), have reported an increased risk of having breast cancer diagnosed in women taking oestrogens, oestrogen-progestagen combinations or tibolone for HRT for several years (see Section 4.8).
For all HRT, an excess risk becomes apparent within a few years of use and increases with duration of intake but returns to baseline within a few (at most five) years after stopping treatment.
In the MWS, the relative risk of breast cancer with conjugated equine oestrogens (CEE) or estradiol (E2) was greater when a progestagen was added, either sequentially or continuously, and regardless of type of progestagen. There was no evidence of a difference in risk between the different routes of administration.
In the WHI study, the continuous combined conjugated equine oestrogen and medroxyprogesterone acetate (CEE + MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.
HRT, especially oestrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
Venous Thromboembolism (VTE)
HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. One randomised controlled trial and epidemiological studies found a two- to threefold higher risk for users compared with non-users. For non-users it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged between 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate = 4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later.
Generally recognised risk factors for VTE include a personal or family history, severe obesity (Body Mass Index >30 kg/m2) and systemic lupus erythmatosus (SLE). There is no consensus about the possible role of varicose veins in VTE.
Patients with a risk of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.
The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all post-operative patients scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4 to 6 weeks earlier, if this is possible. Treatment should not be restarted until the woman is completely mobilised.
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 cardiovascular benefit with continuous combined conjugated oestrogens and medroxyprogesterone acetate (MPA). Two large clinical trials (WHI and HERS i.e. Heart and Estrogen/progestin Replacement Study) showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products there are only limited data from randomised controlled trials examining effects in cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.
Stroke
One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated oestrogens and MPA. For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50–59 years and 11 per 1000 women aged 60-69 years. It is estimated that for women who use conjugated oestrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate = 1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.
Ovarian cancer
Long term (at least 5-10 years) use of oestrogen-only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRT's confers to a different risk than oestrogen-only products.
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. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).
There is no conclusive evidence for improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65. It is unknown whether the findings apply to younger postmenopausal women or other HRT products.
In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.
Hormonal contraception should be stopped when treatment with Cyclo-Progynova is started and the patient should be advised to take non-hormonal contraceptive precautions.
Lactose
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorbtion 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 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 following symptoms have been reported during use of Cyclo-Progynova:
Reproductive System – breast tenderness, breast enlargement, breakthrough bleeding, spotting
Gastrointestinal System – increased appetite, bloating, nausea, vomiting, dyspepsia
Skin Disorders – rashes
Nervous System – anxiety, depressive symptoms, dizziness, altered libido, headache
Other – altered weight, oedema, leg cramps, palpitations
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
* According to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women's Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users.
For oestrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which >80% of HRT use was oestrogen-only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95%CI 1.21-1.49) and 1.30 (95%CI 1.21-1.40), respectively.
For oestrogen plus progestagen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with oestrogens alone.
The MWS reported that, compared to never users, the use of various types of oestrogen-progestagen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of oestrogens alone (RR = 1.30, 95%CI: 1.21 – 1.40) or use of tibolone (RR=1.45; 95%CI 1.25-1.68).
The WHI trial reported a risk estimate of 1.24 (95%CI 1.01 – 1.54) after 5.6 years of use of oestrogen-progestagen combined HRT (CEE + MPA) in all users compared with placebo.
The absolute risks calculated from the MWS and the WHI trial are presented below:
The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:
• For women not using HRT, about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years.
• For 1000 current or recent users of HRT, the number of additional cases during the corresponding period will be
• For users of oestrogen-only replacement therapy
between 0 and 3 (best estimate = 1.5) for 5 years' use
between 3 and 7 (best estimate = 5) for 10 years' use.
• For users of oestrogen plus progestagen combined HRT,
between 5 and 7 (best estimate = 6) for 5 years' use
between 18 and 20 (best estimate = 19) for 10 years' use.
The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to oestrogen-progestagen combined HRT (CEE + MPA) per 10,000 women years.
According to calculations from the trial data, it is estimated that:
• For 1000 women in the placebo group, about 16 cases of invasive breast cancer would be diagnosed in 5 years.
• For 1000 women who used oestrogen + progestagen combined HRT (CEE + MPA), the number of additional cases would be between 0 and 9 (best estimate = 4) for 5 years' use.
The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) (see section 4.4).'
Endometrial Cancer
** In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed oestrogens. According to data from epidemiological studies, the best estimate of the risk is that for women not using HRT, about 5 in every 1000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. Depending on the duration of treatment and oestrogen dose, the reported increase in endometrial cancer risk among unopposed oestrogen users varies from 2-to 12-fold greater compared with non-users. Adding a progestagen to oestrogen-only therapy greatly reduces this increased risk.
4.9 Overdose
There have been no reports of ill-effects from overdosage. There are no specific antidotes, and therefore treatment should be symptomatic.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Cyclo-Progynova contains synthetic estradiol valerate, (the valeric-acid ester of the endogenous female oestrogen, estradiol) and the synthetic progestagen, Norgestrel.
Estradiol valerate, synthetic 17β-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.
As oestrogens promote growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestagen reduces, but does not eliminate the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.
Oestrogens prevent bone loss following menopause or ovariectomy.
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 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 this is limited.
5.2 Pharmacokinetic Properties
Following oral administration to man, estradiol valerate is rapidly and completely absorbed by the gastrointestinal tract. It is metabolised during absorption and the first pass through the liver into estradiol and its metabolites estrone and estriol. The systemic bioavailability of estradiol is approximately 3% of the dose. The metabolites are mainly excreted in the urine, about 10% of the dose being excreted in the faeces.
Following a single administration of 2 mg orally, a peak estradiol plasma concentration of approximately 50-65 pg/ml is achieved after 3-6 hours. This plasma level may remain elevated for up to 48 hours. Due to daily administration with Cyclo-Progynova the serum levels of estradiol may reach 100-150 pg/ml.
Norgestrel is similarly absorbed from the gastrointestinal tract, metabolised by the liver and excreted in the urine and faeces as glucuronide and sulphate conjugates.
After termination of treatment the estradiol and norgestrel serum levels drop to baseline values within 2 days.
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 And Other Handling
None stated.
7. Marketing Authorisation Holder
Meda Pharmaceuticals Ltd
Skyway House
Parsonage Road
Takeley
Bishop's Stortford
CM22 6PU
8. Marketing Authorisation Number(S)
PL 15142/0067
9. Date Of First Authorisation/Renewal Of The Authorisation
20 10 02
10. Date Of Revision Of The Text
14 March 2011
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