CYCLO-PROGYNOVA Special Precautions
CYCLO-PROGYNOVA Special Precautions
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.
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
- risk factors for oestrogen dependent tumours, e.g. 1st degree heredity for breast cancer
- liver disorders (e.g. liver adenoma)
- diabetes mellitus with or without vascular involvement
- migraine or severe headache
- systemic lupus erythematosus
- a history of endometrial hyperplasia
- 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
- jaundice or deterioration in liver function.
- migrainous headaches occur for the first time
The risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods. 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.
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.
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.
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.
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.
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.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorbtion should not take this medicine.
CYCLO-PROGYNOVA Adverse Reactions
CYCLO-PROGYNOVA Adverse Reactions
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* and endometrial** 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 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
- In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.
* 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).'
** 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.