- 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 Fertility, 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
PosologyIn women receiving estrogen replacement therapy there is an increased risk of endometrial cancer which can be countered by progesterone administration.The recommended dose is 200 mg daily at bedtime, for twelve days in the last half of each therapeutic cycle (beginning on Day 15 of the cycle and ending on Day 26). Withdrawal bleeding may occur in the following week.Alternatively 100 mg can be given at bedtime from Day 1 to Day 25 of each therapeutic cycle, withdrawal bleeding being less with this treatment schedule.
Paediatric populationThere is no relevant use of Utrogestan in the paediatric population.
Older peopleAs for adults
Method of Administration:OralUtrogestan 100mg Capsules should not be taken with food and should be taken at bedtime.Concomitant food ingestion increases the bioavailability of micronized progesterone.
Warnings:• 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.Utrogestan 100 mg Capsules are not suitable:• in the treatment of premature labour, or • as a contraceptive.
Medical examination/follow-upBefore 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 and warnings for use. 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 which 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 supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Utrogestan 100 mg Capsules, in particular:• Leiomyoma (uterine fibroids) or endometriosis• Risk factors for thromboembolic disorders (see below)• Risk factors for estrogen 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• Fluid retention (e.g. cardiac disease, renal disease)• Depression• Photosensitivity
Reasons for immediate withdrawal of therapyTherapy should be discontinued in case a contra-indication is discovered and in the following situations: • Jaundice or deterioration in liver function• Significant increase in blood pressure • New onset of migraine-type headache• Sudden or gradual, partial or complete loss of vision• Proptosis or diplopia• Papilloedema• Retinal vascular lesions
Endometrial hyperplasia and carcinomaIn women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among estrogen-only users varies from 2-to 12-fold greater compared with non-users, depending on the duration of treatment and estrogen dose (see section 4.8). After stopping treatment risk may remain elevated for at least 10 years. The addition of progesterone for at least 12 days per month/28 day cycle or continuous combined estrogen-progestagen therapy in non-hysterectomised women prevents the excess risk associated with estrogen-only HRT. Breakthrough bleeding and spotting may occur during the first months of treatment. If breakthrough bleeding persists, a lower dose of Utrogestan for 25 days per cycle could be considered (see section 4.2).If breakthrough bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.
Breast cancerThe overall evidence suggests an increased risk of breast cancer in women taking combined estrogen-progestagen and possibly also estrogen-only HRT, that is dependent on the duration of taking HRT.
Combined estrogen-progestagen therapy• The randomised placebo-controlled trial the (Women's Health Initiative study (WHI), and epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined estrogen-progestagen for HRT that becomes apparent after about 3 years (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 estrogen-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. Long-term (at least 5-10 years) use of estrogen-only HRT products has been associated with a slightly increased risk of ovarian cancer (see section 4.8). Some studies including the WHI trial suggest that the long-term use of combined HRTs may confer a similar, or slightly smaller, risk (see Section 4.8).
Venous thromboembolismHRT 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 (see 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 estrogens, older age, major surgery, prolonged immobilisation, obesity (BMI > 30 kg/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 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 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 a leg, sudden pain in the chest, dyspnoea).
Coronary artery 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.
Ischaemic strokeCombined estrogen-progestagen and estrogen-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 conditionsHRT use does not improve cognitive function. There is some evidence of increased risk of probable dementia in women who start using continuous combined or estrogen-only HRT after the age of 65.
PregnancyOral Utrogestan 100mg Capsules are not indicated during pregnancy.If pregnancy occurs during medication, Utrogestan 100mg Capsules should be withdrawn immediately.Clinically, data on a large number of exposed pregnancies indicate no adverse effects of progesterone on the foetus. The results of most epidemiological studies to date relevant to inadvertent foetal exposure to combinations of estrogens + progesterone indicate no teratogenic or foetotoxic effect.Prescription of progesterone beyond the first trimester of pregnancy may reveal gravidic cholestasis.
Breast-feedingUtrogestan 100 mg Capsules is not indicated during breast-feeding.Detectable amounts of progesterone enter the breast milk.
|System organ class||Common ≥1/100; <1/10||Uncommon ≥1/1000; ≤1/100||Rare ≥1/10000; ≤1/1000||Very rare ≤1/10000|
|Reproductive system and breast disorders||Altered periods Amenorrhoea Intercurrent bleeding||.Mastodynia|
|Nervous system disorders||Headaches||Drowsiness Dizziness||Depression|
|Gastrointestinal disorders||Vomiting Diarrhoea Constipation||Nausea|
|Hepatobiliary disorders||Cholestatic jaundice|
|Immune system disorders||Urticaria|
|Skin and subcutaneous tissue disorders||Pruritus Acne||Chloasma|
When used in conjunction with oestrogen, the following apply.
Breast cancer riskAn up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined estrogen-progestagen therapy for more than 5 years. Any increased risk in users of estrogen-only therapy is substantially lower than that seen in users of estrogen-progestagen combinations. The level of risk is dependent on the duration of use (see section 4.4).Results of the largest randomised placebo-controlled trial (WHI-study) and largest epidemiological study (MWS) are presented.
Million Women study Estimated additional risk of breast cancer after 5 years' use
|Age range (years)||Additional cases per 1000 never-users of HRT over a 5 year period*2||Risk ratio & 95%CI#||Additional cases per 1000 HRT users over 5 years (95%CI)|
|EstrogenEstrogen only HRT|
|#Overall risk ratio. The risk ratio is not constant but will increase with increasing duration on use Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately. the TC we finally decided to re-include the figures of table 2 of the Million Women study.|
US WHI studies - additional risk of breast cancer after 5 years' use
|Age range (years)||Incidence per 1000 women in placebo arm over 5 years||Risk ratio & 95%CI||Additional cases per 1000 HRT users over 5 years (95%CI)|
|50-79||21||0.8 (0.7 1.0)||-4 (-6 0)*3|
|CEE+MPA estrogen & progestagen|
|50-79||17||1.2 (1.0 1.5)||+4 (0 9)|
Ovarian cancerLong-term use of estrogen-only and combined estrogen-progestagen HRT has been associated with a slightly increased risk of ovarian cancer. In the Million Women Study 5 years of HRT resulted in 1 extra case per 2500 users.
Risk of venous thromboembolismHRT 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
|Age range (years)||Incidence per 1000 women in placebo arm over 5 years||Risk ratio & 95%CI||Additional cases per 1000 HRT users|
|50-59||7||1.2 (0.6 2.4)||1 (-3 10)|
|Oral combined estrogen-progestagen|
|50-59||4||2.3 (1.2 4.3)||5 (1 13)|
Risk of ischaemic strokeThe use of estrogen-only and estrogen + 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*5 over 5 years' use
|Age range (years)||Incidence per 1000 women in placebo arm over 5 years||Risk ratio & 95%CI||Additional cases per 1000 HRT users|
|50-59||8||1.3 (1.1 1.6)||3 (1 5)|
Other adverse reactions that have been reported in association with estrogen / progestagen treatment• Rashes,• Weight changes,• Changes in libido,• Skin and subcutaneous disorders: erythema multiforme, erythema nodosum, vascular purpura.• Pyrexia,• Insomnia,• Alopecia,• Hirsutism;• Gall bladder disease.• Probable dementia over the age of 65 (see section 4.4).
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 website www.mhra.gov.uk/yellowcard.
AbsorptionMicronised progesterone is absorbed by the digestive tract. Pharmacokinetic studies conducted in healthy volunteers have shown that after oral administration of 2 capsules (200mg), plasma progesterone levels increased to reach the Cmax of 13.8ng/ml +/- 2.9ng/ml in 2.2 +/- 1.4 hours. The elimination half-life observed was 16.8+/- 2.3 hours.
DistributionProgesterone is approximately 96%-99% bound to serum proteins, primarily to serum albumin (50%-54%) and transcortin (43%-48%).
EliminationUrinary elimination is observed for 95% in the form of glycuroconjugated metabolites, mainly 3 α, 5 βpregnanediol (pregnandiol).
BiotransformationProgesterone is metabolised primarily by the liver. The main plasma metabolites are 20 α hydroxy- ∆ 4 α- prenolone and 5 α-dihydroprogesterone. Some progesterone metabolites are excreted in the bile and these may be deconjugated and further metabolised in the gut via reduction, dehydroxylation and epimerisation. The main plasma and urinary metabolites are similar to those found during the physiological secretion of the corpus luteum.
Linearity/non-linearityThe pharmacokinetics of micronized progesterone is independent of the dose administered. Although there were some inter-individuals variations, the same individual pharmacokinetic characteristics were maintained over several months permitting appropriate individual adaptation of the posology and indicating predictable responses to the drug.
Older peopleAs per adults above
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