- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
|White Tablets||-||2mg estradiol valerate|
|Pale Brown Tablets||-||500 micrograms norgestrel|
|2mg estradiol valerate|
Children and adolescentsCyclo-Progynova is not indicated for use in children and adolescents.
Geriatric patientsThere 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).
Patients with hepatic impairmentCyclo-Progynova has not been specifically studied in patients with hepatic impairment. (see 4.3 Contraindications).
Patients with renal impairmentCyclo-Progynova has not been specifically studied in renally impaired patients. Available data do not suggest a need for dosage adjustment in this patient population.
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 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.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 supervisionIf 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- Chorea minor- a history of endometrial hyperplasia (see below)- epilepsy- asthma- otosclerosis- hereditary angioedemaClose medical supervision (including periodic measurement of prolactin levels) is necessary if the patient suffers from prolactinoma.
Reasons for immediate withdrawal of therapyTherapy 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.- migrainous headaches occur for the first time
Endometrial HyperplasiaIn 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 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 CancerThe overall evidence suggests an increased risk of breast cancer in women taking combined oestrogenprogestagen and possibly also oestrogen-only HRT, that is dependent on the duration of taking HRT.Combined oestrogen-progestagen therapyThe randomised placebo-controlled trial the (Women's Health Initiative study), and 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 years (see section 4.8).Oestrogen-only therapyThe 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 substantially lower than that found in users of oestrogen-progestagen combinations (see section 4.8).The excess risk becomes apparent within a few years of use but returns to baseline within a few (at most five) years after stopping treatment.HRT, especially oestrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
Ovarian cancerOvarian 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 the long-term use of combined HRTs may be associated with a similar, or slightly smaller, risk (see section 4.8).
Venous Thromboembolism (VTE)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 HRTIf 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 therapyThe 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-onlyRandomised controlled data found no increased risk of CAD in hysterectomised women using oestrogen-only therapy.Ischaemic StrokeCombined 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).
Liver tumorIn rare cases benign, and even more rarely, malignant liver tumors have been observed after the use of hormonal substances such as those contained in HRT products. In isolated cases, these tumors led to life-threatening intra-abdominal hemorrhage. A hepatic tumor should be considered in the differential diagnosis if upper abdominal pain, enlarged liver, or signs of intra-abdominal haemorrhage occur.
Other ConditionsOestrogens 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.Cyclo-Progynova cannot be used as a contraceptive.Hormonal contraception should be stopped when treatment with Cyclo-Progynova is started and the patient should be advised to take non-hormonal contraceptive precautions.In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.
LactosePatients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorbtion should not take this medicine.
|System Organ Class MedDRA v 8.0||Common (≥1/100, <1/10)||Uncommon (≥1/1,100, < 1/100)||Rare (≥1/10,000, <1/1,000)|
|Immune system disorders||Hypersensitivity reaction|
|Metabolism and nutrition disorders||Weight increase or Weight decrease|
|Psychiatric disorders||Depressed mood||Anxiety, Libido decreased or Libido increased|
|Nervous system disorders||Headache||Dizziness||Migraine|
|Eye disorders||Visual disturbances||Contact lens intolerance|
|Gastrointestinal disorders||Abdominal pain, Nausea||Dyspepsia||Bloating, Vomiting|
|Skin and subcutaneous tissue disorders||Rash, Pruritus||Erythema nodosum, Urticaria||Hirsutism, Acne|
|Musculoskeletal and connective tissue disorders||Muscle cramps|
|Reproductive system and breast disorders||Uterine/Vaginal bleeding including Spotting (bleeding irregularities usually subside during continued treatment)||Breast pain, Breast tenderness||Dysmenorrhea, Vaginal discharge, Premenstrual-like syndrome, Breast enlargement,|
|General disorders and administration site conditions||Edema||Fatigue|
Reporting of suspected adverse reactionsReporting 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
NorgestrelAbsorptionAfter 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.DistributionOn 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.EliminationThe 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 conditionsBased 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.
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