Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Besins Healthcare, Avenue Louise 287, B-1050 Brussels, Belgium
When used in conjunction with estrogens, Utrogestan should not be used in patients with any of the following conditions:
Utrogestan 100 mg Capsules are not suitable:
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 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.
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 supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Utrogestan 100 mg Capsules, in particular:
Therapy should be discontinued in case a contra-indication is discovered and in the following situations:
In 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-progestogen 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.
The overall evidence suggests an increased risk of breast cancer in women taking combined estrogen-progestogen and possibly also estrogen-only HRT, that is dependent on the duration of taking HRT.
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-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
Ovarian cancer is much rarer than breast cancer. Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking estrogen-only or combined estrogen-progestogen 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).
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 (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).
There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined estrogen-progestogen or estrogen-only HRT.
Combined estrogen-progestogen 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).
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 estrogen-only HRT after the age of 65.
Drugs known to induce the hepatic CYP450-3A4 such as barbiturates, anti-epileptic agents (phenytoin, carbamazepine), rifampicin, phenylbutazone, bromcriptine, spironolactone, griseofulvin, some antibiotics (ampicillins, tetracyclines) and also herbal products containing St. John’s wort, (Hypericum perforatum) may increase metabolism and the elimination of progesterone.
Ketokonazole and other inhibitors of CYP450-3A4 such as ritonavir and nelfinavir may increase bioavailability of progesterone. The metabolism of progesterone by human liver microsomes was inhibited by ketoconazole (IC50 <0.1 μM).
Progesterone may raise the plasma concentration of ciclosporin.
Aminoglutethimide markedly reduces the plasma concentrations of medroxyprogesterone acetate and megestrol, possibly through a hepatic enzyme-inducing effect.
Progesterone may enhance or reduce the anticoagulant effect of coumarins.
Progesterone antagonises the anticoagulant effect of phenindione.
An adjustment in anti-diabetic dosage may be required for women being treated concomitantly with progesterone.
The concomitant use of ulipristal acetate with progesterone may result in reduced efficacy of progesterone.
Progesterone may increase the plasma concentration of diazepam.
Progesterone may increase the plasma concentration of tizanidine.
There have been occasional reports of breakthrough bleeding when terbinafine is used concomitantly with progesterone.
Progesterone may affect the results of laboratory tests of hepatic and/or endocrine functions.
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.
Utrogestan 100 mg Capsules is not indicated during breast-feeding (see section 4.3).
Progesterone is distributed into breast milk.
Not relevant.
This medicine may cause drowsiness or dizziness; therefore care should be taken when driving or using machines.
The reporting rate of adverse drug reactions with Utrogestan Oral and Vaginal formulations was calculated as 1.43/1,000 patient year’s corresponding to approximately 1.5 spontaneously reported cases in every 1000 patients exposed to Utrogestan (Periodic Benefit Risk Evaluation Report 01 January 2012 – 31 December 2017).
The table below lists adverse experiences which were reported in > 10% of patients (regardless of relationship to treatment) who received cyclic micronized Progesterone capsules, 200 mg daily (12 days per calendar month cycle) with daily 0.625 mg conjugated estrogen, in a multicenter, randomised, double-blind, placebo-controlled clinical trial (Postmenopausal Estrogen and Progestin Interventions (PEPI) Trial) in 875 postmenopausal women.
Adverse experiences (>10%) reported in an 875 patient placebo-controlled trial in postmenopausal women over a 3-year period:
| System Organ Class | Preferred Term | Micronized progesterone capsules 200 mg with conjugated estrogens 0.625 mg (N=178) | Conjugated estrogens 0.625 mg (only) (N=175) | Placebo (N=174) |
|---|---|---|---|---|
| Gastrointestinal disorders | Abdominal bloating | 12 | 10 | 5 |
| Abdominal pain | 10 | 13 | 10 | |
| Nervous system disorders | Headache | 31 | 30 | 27 |
| Dizziness | 15 | 5 | 9 | |
| Psychiatric disorders | Depression | 19 | 18 | 12 |
| Reproductive system and breast disorders | Breast tenderness | 27 | 16 | 6 |
| Hot flushes | 11 | 14 | 35 | |
| Vaginal discharge | 10 | 10 | 3 | |
| Miscellaneous | Joint pain | 20 | 22 | 29 |
| Urinary problems | 11 | 10 | 9 |
The information given below is based on extensive post marketing experience, primarily from oral administration of progesterone.
Adverse effects have been ranked under headings of frequency using the following convention: very common (≥1/10); common (≥1/100; <1/10); uncommon (≥1/1,000;<1/100); rare (≥1/10,000;<1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data).
| System organ class | Frequency Not known (cannot be estimated from the available data) |
|---|---|
| Gastrointestinal disorders | Abdominal pain, Nausea |
| General disorders and administration site conditions | Fatigue |
| Nervous system disorders | Headache, Somnolence, Dizziness |
| Reproductive system and breast disorders | Vaginal haemorrhage |
| Skin and subcutaneous tissue disorders | Pruritus |
Somnolence or transient dizziness may occur 1 to 3 hours after intake of the drug. Bedtime dosing and reduction of the dose may reduce these effects.
The following risks apply in relation to systemic estrogen/progestogen treatment:
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) |
|---|---|---|---|
| Estrogen only HRT | |||
| 50-65 | 9-12 | 1.2 | 1-2 (0-3) |
| Combined estrogen-progestogen | |||
| 50-65 | 9-12 | 1.7 | 6 (5-7) |
# 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.
2*T aken from baseline incidence rates in developed countries
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) |
|---|---|---|---|
| CEE estrogen-only | |||
| 50-79 | 21 | 0.8 (0.7 – 1.0) | -4 (-6 – 0)*3 |
| CEE+MPA estrogen & progestogen‡ | |||
| 50-79 | 17 | 1.2 (1.0 – 1.5) | +4 (0 – 9) |
‡ When 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.
3* WHI study in women with no uterus, which did not show an increase in risk of breast cancer
The endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT.
In women with a uterus, use of estrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4).
Depending on the duration of estrogen-only use and estrogen 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 progesterone to estrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study (MWS) 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)).
Use of estrogen-only and combined estrogen-progestogen 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 (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 over a 5-year period.
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:
| Age range (years) | Incidence per 1000 women in placebo arm over 5 years | Risk ratio & 95%CI | Additional cases per 1000 HRT users |
|---|---|---|---|
| Oral estrogen-only*4 | |||
| 50-59 | 7 | 1.2 (0.6 – 2.4) | 1 (-3 – 10) |
| Oral combined estrogen-progestogen | |||
| 50-59 | 4 | 2.3 (1.2 – 4.3) | 5 (1 – 13) |
4* Study in women with no uterus
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) |
5* no differentiation was made between ischaemic and haemorrhagic stroke.
The following adverse reactions have also been reported in association with systemic estrogen/progestogen treatment:
Rash
Urticaria
Chloasma/melasma
Pyrexia
Insomnia
Alopecia
Irregular menstruation
Amenorrhoea
Breast pain/mastodynia
Fluid retention/oedema
Weight changes
Changes in libido
Depression
Gall bladder disease
Probable dementia over the age of 65 (see section 4.4)
Skin and subcutaneous disorders: erythema multiforme, erythema nodosum, vascular purpura.
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 website www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
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