This information is intended for use by health professionals

1. Name of the medicinal product

UTROGESTAN VAGINAL 200MG CAPSULES

2. Qualitative and quantitative composition

Each capsule contains 200 mg progesterone (micronised).

Excipients with known effect: Soya lecithin

For a full list of excipients, see Section 6.1.

3. Pharmaceutical form

Vaginal Capsules, soft

Ovoid and slightly yellow soft capsules, containing whitish oily suspension.

4. Clinical particulars
4.1 Therapeutic indications

Utrogestan Vaginal 200 mg Capsules is indicated in women for supplementation of the luteal phase during Assisted Reproductive Technology (ART) cycles.

4.2 Posology and method of administration

Posology

The recommended dosage is 600 mg/day, in three divided doses, from the day of embryo transfer until at least the 7th week of pregnancy and not later than the 12th week of pregnancy.

Paediatric population

There is no relevant use of Utrogestan Vaginal 200 mg Capsules in the paediatric population.

Older people

There is no relevant use of Utrogestan Vaginal 200 mg Capsules in older people.

Method of Administration:

Vaginal

Each capsule of Utrogestan Vaginal 200mg must be inserted deep into the vagina.

For dosage, national and local treatment guidelines should be taken into account.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1,

• Severe hepatic dysfunction,

• Undiagnosed vaginal bleeding,

• Mammary or genital tract carcinoma,

• Thrombophlebitis,

• Thromboembolic disorders,

• Cerebral haemorrhage,

• Porphyria.

• Missed abortion

4.4 Special warnings and precautions for use

Warnings:

Utrogestan Vaginal 200mg Capsules should only be used during the first three months of pregnancy and must only be administrated by vaginal route. Prescription of progesterone beyond the first trimester of pregnancy may reveal gravidic cholestasis.

Utrogestan Vaginal 200mg Capsules are not suitable as a contraceptive.

Treatment should be discontinued upon diagnosis of a missed abortion.

Precautions:

Utrogestan Vaginal 200 mg Capsules contains soya lecithin and may cause hypersensitivity reactions (urticarial and anaphylactic shock in hypersensitive patients). As there is a possible relationship between allergy to soya and allergy to peanut, patients with peanut allergy should avoid using Utrogestan Vaginal 200mg Capsules.

4.5 Interaction with other medicinal products and other forms of interaction

Utrogestan Vaginal 200mg Capsules may interfere with the effects of bromocriptine and may raise the plasma concentration of ciclosporin. Utrogestan Vaginal 200mg Capsules may affect the results of laboratory tests of hepatic and/or endocrine functions.

Metabolism of Utrogestan Vaginal 200mg Capsules is accelerated by rifamycin medicines (such as rifampicin) and antibacterial agents.

The metabolism of progesterone by human liver microsomes was inhibited by ketoconazole (IC50 <0.1 μM). Ketoconazole is a known inhibitor of cytochrome P450 3A4. These data therefore suggest that ketoconazole may increase the bioavailability of progesterone. The clinical relevance of the in vitro findings is unknown.

4.6 Fertility, pregnancy and lactation

Pregnancy

No association has been found between the maternal use of natural progesterone in early pregnancy and foetal malformations.

Breastfeeding

Utrogestan Vaginal 200 mg Capsules is not indicated during breast-feeding.

Detectable amounts of progesterone enter the breast milk.

Fertility

As this medicinal product is indicated to support luteal deficiency in subfertile or infertile women, there is no deleterious known effect on fertility.

4.7 Effects on ability to drive and use machines

Utrogestan Vaginal Capsules has negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Post-Marketing experience

The information given below is based on extensive post marketing experience from vaginal administration of progesterone.

Adverse effects have been ranked under headings of frequency using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <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)

Reproductive system and breast disorders

Vaginal haemorrhage

Vaginal discharge

Skin and subcutaneous tissue disorders

Pruritus

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.

4.9 Overdose

Symptoms of overdosage may include somnolence, dizziness, euphoria or dysmenorrhoea. Treatment is observation and, if necessary, symptomatic and supportive measures should be provided.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Sex hormones and modulators of the genital system, progestogens, ATC code: G03DA04.

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 Vaginal 200mg 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.

5.2 Pharmacokinetic properties

Absorption

Following oral administration, micronised progesterone is absorbed by the digestive tract. Pharmacokinetic studies conducted in healthy volunteers have shown that after oral administration of two 100 mg 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.

Although there were inter-individual variations, the individual pharmacokinetic characteristics were maintained over several months, indicating predictable responses to the drug.

Following vaginal administration, micronised progesterone is absorbed rapidly and achieves stable plasma levels in the range of 4-12 ng/ml, depending on the daily dose, with much less inter-subject variation than following oral administration.

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.

Following oral administration, the main plasma metabolites are 20 α hydroxy- Δ 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.

Following vaginal administration, only low plasma levels of pregnanolone and 5α- dihydroprogesterone are detected, due to the lack of first-pass metabolism.

5.3 Preclinical safety data

Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology and toxicity.

6. Pharmaceutical particulars
6.1 List of excipients

Capsule contents:

Sunflower oil, refined

Soybean lecithin

Capsule shell:

Gelatin

Glycerol

Titanium dioxide (E171)

Water, purified

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

The product is supplied in PVC/Aluminium blisters contained in cartons.

Pack sizes: Blister pack containing 15, 21 or 90 capsules.

Not all pack sizes may be marketed

6.6 Special precautions for disposal and other handling

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Besins Healthcare

Avenue Louise, 287

B-1050 Brussels

Belgium

8. Marketing authorisation number(s)

PL 28397/0005

9. Date of first authorisation/renewal of the authorisation

21/12/2012

12/09/2017

10. Date of revision of the text

30 April 2019