Symptoms of overdosage may include somnolence, dizziness, euphoria or dysmenorrhoea. Treatment is observation and, if necessary, symptomatic and supportive measures should be provided.
3 years.
Not applicable.
Sunflower oil, refined
Soya lecithin
Gelatin
Glycerol
Titanium dioxide
Purified water
The information given below is based on extensive post marketing experience, primarily from oral administration of progesterone.
| 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 |
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.
When used in conjunction with oestrogen, the following apply.
Breast cancer risk
An 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.
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 | |||
| 50-65 | 9-12 | 1.2 | 1-2 (0-3) |
| Combined estrogen-progestagen | |||
| 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. 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) |
| CEE estrogen-only | |||
| 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) |
‡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.
2 *Taken from baseline incidence rates in developed countries
3 *WHI study in women with no uterus, which did not show an increase in risk of breast cancer
Endometrial cancer risk
Postmenopausal women with an uterus.
The endometrial cancer risk is about 5 in every 1000 women with an 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.
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)).
Ovarian cancer
Long-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 thromboembolism
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. 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-progestagen | |||
| 50-59 | 4 | 2.3 (1.2 - 4.3) | 5 (1 - 13) |
4 *Study in women with no uterus
Risk of coronary artery disease
The risk of coronary artery disease is slightly increased in users of combined estrogen-progestagen HRT over the age of 60.
Risk of ischaemic stroke
The use of estrogen-only and estrogen + progestagen therapy is associated with an up to 1.5 fold increased relative risk of ischaemic stroke.
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.
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.
Reporting of suspected adverse reactions
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.
Nonclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
Pharmacotherapeutic group (ATC code: G03DA): Progestagens
Mechanism of action
Progesterone is a natural progestogen, the main hormone of the corpus luteum and the placenta. It acts on the endometrium by converting the proliferating phase to the secretory phase. Utrogestan 100mg Capsules have all the properties of endogenous progesterone with induction of a full secretory endometrium and in particular gestagenic, antiestrogenic, slightly anti-androgenic and antialdosterone effects.
Clinical efficacy and safety
As estrogens promote the growth of the endometrium, unopposed estrogens increase the risk of endometrial hyperplasia and cancer. The addition of progesterone greatly reduces the estrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.
Absorption
Micronised 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.
Distribution
Progesterone is approximately 96%-99% bound to serum proteins, primarily to serum albumin (50%-54%) and transcortin (43%-48%).
Elimination
Urinary elimination is observed for 95% in the form of glycuroconjugated metabolites, mainly 3 α, 5 β-pregnanediol (pregnandiol).
Biotransformation
Progesterone 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-linearity
The 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 people
As per adults above
14 July 2017
Besins Healthcare
Avenue Louise, 287
B-1050 Brussels
Belgium
No special precautions for storage.
The product is supplied in PVC/Aluminium blisters contained in cartons.
Pack size: 30 capsules
PL 28397/0003
Utrogestan 100mg Capsules may cause drowsiness and/or dizziness in a minority of patients; therefore caution is advised in drivers and users of machines. Taking the capsules at bedtime should reduce these effects during the day.
Any unused product or waste material should be disposed of in accordance with local requirements.
Date of first authorisation: 10/01/2003
Date of renewal: 27/03/2009
