Utrogestan

The active substance is: Micronized progesterone.
Utrogestan 100 mg: Round and slightly yellow soft capsules, containing whitish oily suspension.
Utrogestan 200 mg: Ovoid and slightly yellow soft capsules, containing whitish oily suspension.
Excipients/Inactive Ingredients: Excipients of the contents of the capsule: Sunflower oil, soya-bean lecithin.
Constituents of the capsules: Gelatin, glycerol, titanium dioxide (E 171).

Pharmacotherapeutic group: Genito-urinary system and sex hormones. ATC code: G03DA04.
Pharmacology: Pharmacodynamics: 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 Capsules have all the properties of endogenous progesterone with induction of a full secretory endometrium and in particular gestagenic, antiestrogenic, slightly, antiandrogenic and antialdosterone effects.
Clinical Trials: Adjunctive use with an oestrogen in postmenopausal women with an intact uterus (for hormone replacement therapy/HRT): Two company-sponsored studies have been conducted to investigate efficacy of Utrogestan during hormone replacement therapy.
1. Study Lorrain 1994 was an open-label, single-centre, randomised, parallel-group, prospective trial that evaluated and compared the efficacy, safety and tolerance of Utrogestan and medroxyprogesterone acetate (MPA) in menopausal women receiving transdermal oestriadiol for a period of at least 13 cycles.
This clinical study was on open-label, single-centre, randomised, parallel-group, prospective trial.
Postmenopausal women were randomised to treatment with Utrogestan 200 mg/day (two 100 mg oral tablets taken at bedtime) or MPA (Provera) 10 mg/day (one 10 mg tablet taken at bedtime). Utrogestan or MPA were taken from Day 14 to Day 25. All women received 17-β-estradiol 0.05 mg/day patches that were applied twice weekly from Day 1 to Day 25.
The efficacy outcome measures assessed were bleeding patterns. A total of 40 women were randomised to receive Utrogestan (n=20) or MPA (n=20). The incidence of amenorrheic cycles was greater in women treated with Utrogestan (42/215 cycles, 19.5%) versus MPA (6/178, 3.4%). The incidence of breakthrough bleeding was similar in women treated with Utrogestan (7/222, 3.2%) versus MPA (8/181, 4.4%).
Menstruation occurred earlier, was less abundant, and of shorter duration in women treated with Utrogestan versus MPA (see Table 1).


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In conclusion, the use of Utrogestan (progesterone) for postmenopausal HRT produced more desirable bleeding patterns than MPA.
2. Study Moyer 1987 was a 5-year, open-label, non-controlled, single-centre, observational study that evaluated the endometrial situation of patients who regularly used combinations of Oestrogel (E2) and Utrogestan (P4) for at least 5 years. The primary outcome for this study was endometrial histology in response to treatment with HRT.
This was a 5-year, open-label, non-controlled, single-centre, observational study. Women were administered combinations of percutaneous oestrogen (Oestrogel) at either 1.5 mg/day or 3 mg/day on Days 1 to 21 of their cycle and oral Utrogestan capsules at either 200 mg/day or 300 mg/day on Days 8 to 21 of their cycle for at least 5 years. Initially, women were administered Oestrogel 1.5 mg/day plus Utrogestan 200 mg/day. The dose of Oestrogel was increased to 3.0 mg/day if optimal improvement in clinical menopause symptoms was not obtained within the first 6 months of treatment. The dose of Utrogestan was increased to 300 mg/day if cyclic withdrawal bleeding was not occurring during the first 6 months of treatment and women preferred cyclic withdrawal bleeding.
In conclusion, Oestrogel and Utrogestan resulted in favourable bleeding patterns with higher doses of Oestrogel and Utrogestan resulting in a higher incidence of cyclic bleeding.
Findings from the efficacy analysis provided strong evidence for the use of oral progesterone in combination with oestrogen for HRT in postmenopausal women with an intact uterus. These findings were based primarily on the pivotal company-sponsored studies showing favourable bleeding patterns with Utrogestan and a Cochrane review meta-analysis of data from placebo-controlled RCTs ^{[Maclennan et al, 2004]}, which was considered to be a high quality. Findings from the meta-analysis of 6 placebo-controlled RCTs showed a significant reduction in the frequency and severity of hot flushed in peri or postmenopausal women receiving oral oestrogen in combination with progestogens compared with placebo for at least 3 months. The most recent guidelines from the British Menopause Society ^{[Panay et al, 2013]}, recommend that transdermal preparations should be used in high-risk women who require HRT and that micronized progesterone or dydrogesterone are suitable options when a progestogen is required. Overall, the aim is to replace hormones to as close to physiological levels as possible.
The body of evidence from national guidelines from Australia ^{[RANZCOG, 2011]}, Canada ^{[Reid et al, 2009]}, and the US ^{[NAMS, 2012]}, and international guidelines ^{[Baber 2016, de Villiers 2016]} suggest that HRT is the most effective treatment for controlling menstrual cycles and for reducing vasomotor symptoms, including hot flushed and night sweats, in postmenopausal women with an intact uterus.
Pharmacokinetics: Absorption: Micronized progesterone is absorbed by the digestive tract.
Table 2 summarizes the mean pharmacokinetic parameters in postmenopausal women after five oral daily doses of Utrogestan Capsules 100 mg as a micronized soft-gelatin capsule formulation. (See Table 2.)


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Serum progesterone concentrations appeared linear and dose proportional following multiple dose administration of Utrogestan Capsules 100 mg over the dosage range 100 mg per day to 300 mg per day in postmenopausal women.
Pharmacokinetic studies conducted in healthy volunteers have shown that after oral administration of 2 capsules (200 mg), plasma progesterone levels increase to reach the Cmax of 13.8 ng/mL +/- 2.9 ng/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.
Distribution: Progesterone is approximately 96%-99% bound to serum proteins, primarily to serum albumin (50%-54%) and transcortin (43%-48%).
Metabolism: Progesterone is metabolised primarily by the liver. The main plasma metabolites are 20α-hydroxy-4α-prenolone and 5α-dihydroprogesterone. Some progesterone metabolites are excreted in the bile and these may be deconjugated and further metabolized in the gut via reduction, dehydroxylation and epimerization. The main plasma and urinary metabolites are similar to those found during the physiological secretion of the corpus luteum.
Elimination: Urinary elimination is observed for 95% in the form of glycuro-conjugated metabolites, mainly 3α, 5β-pregnanediol (pregnandiol).

Utrogestan is prescribed for disorder related to a progesterone deficit: By oral route: Menstrual irregularity due to dysovulation, Hormone replacement therapy - adjunctive use with an oestrogen in postmenopausal women with an intact uterus.
By vaginal route: During in Vitro fertilization cycles (IVF).
For all other Progesterone indications, the vaginal route represents an alternative to the oral route, in case of adverse events due to Progesterone (somnolence, dizziness).

Utrogestan should not be taken more than 200 mg per intake (two 100 mg capsules or one 200 mg capsule), by oral or vaginal route.
On average for progesterone insufficiencies, the daily dose is 200 to 300 mg divided into one or two intakes, 100 mg in the morning, and 100 mg or 200 mg at bedtime. In some case, notably to help pregnancy, doctor may has to increase the dose to 600 mg per day, divided into three intakes.
Treatment may be prescribed continuously, or sequentially for some days per month, and possibly associated with estrogen therapy. Two routes of administration are possible, oral and vaginal.
In women receiving oestrogen replacement therapy with intact uterus, the adjunctive use of progesterone at a dose of 200 mg daily at bedtime should be administered 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.
Duration of treatment: The duration of the treatment will be specified by the doctor, according to the case. The duration of treatment may be readjusted by the doctor depending on the indication and efficacy or treatment.
Children: Not applicable.
Method of administration: If the medicine is to be administered orally: Swallow the capsule(s) with a glass of water far from mealtime, in one to three intakes, following doctor's prescription.
If the medicine is to be administered vaginally: Insert each capsule deeply in the vagina.

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

Known allergy or hypersensitivity to progesterone or to any of the excipients. The capsule contains sunflower oil and should never be used by patients allergic to sunflower. Severe hepatic dysfunction, undiagnosed vaginal bleeding, mammary or genital tract carcinoma. Thrombophlebitis, thromboembolic disorder, cerebral haemorrhage, porphyria.

Utrogestan Capsules are not a treatment for premature labour.
Prescription of progesterone beyond the first trimester of pregnancy may reveal gravidic cholestasis.
Utrogestan Capsules are not suitable for use as a contraceptive.
If unexplained, sudden or gradual, partial or complete loss of vision, proptosis or diplopia, papilloedema, retinal vascular lesions or migraine occur during therapy, the drug should be discontinued, and appropriate diagnostic and therapeutic measures instituted.
Utrogestan Capsules are intended to be co-prescribed with an estrogen product as HRT. Epidemiological evidence suggests that the use of HRT is associated with an increased risk of developing deep vein thrombosis (DVT) or pulmonary embolism. The prescribing information for the co-prescribed estrogen product should be referred to for information about the risks of venous thromboembolism.
There is suggestive evidence of a small increased risk of breast cancer with estrogen replacement therapy. It is not known whether concurrent progesterone influences the risk of cancer in post-menopausal women taking hormone replacement therapy. The prescribing information for the co-prescribed estrogen product should be referred to for information about the risks of breast cancer.

Prior to taking hormone replacement therapy (and at regular intervals thereafter) each woman should be assessed. A personal and family medical history should be taken, and physical examination should be guided by this and by the contraindications and warning for this product.
Utrogestan Capsules should not be taken with food and should be taken at bedtime. Concomitant food ingestion increases the bioavailability of Utrogestan Capsules.
Utrogestan Capsules should be used cautiously in patients with conditions that might be aggravated by fluid retention (e.g. hypertension, cardiac disease, renal disease, epilepsy, migraine, asthma); in patients with a history of depression, diabetes, mild to moderate hepatic dysfunction, migraine or photosensitivity and in breast-feeding mothers.
Clinical examination of the breasts and pelvic examination should be performed where clinically indicated rather than as a routine procedure. Women should be encouraged to participate in the national breast cancer screening programme (mammography) and the national cervical cancer screening programme (cervical cytology) as appropriate for their age.
Breast awareness should also be encouraged, and women advised to report any changes in their breasts to their doctor or nurse.
Effects on ability to drive and use machines: Utrogestan 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.

Pregnancy: The use of Utrogestan soft capsules is not contraindicated during pregnancy including the first few weeks.
Lactation: Detectable amounts of progesterone enter the breast milk. There is no indication for prescribing HRT during lactation.

Somnolence or transient dizziness may occur 1 to 3 hours after intake of the drug. Bedtime dosing and reduction of the dose reduce these effects.
Shortening of the cycle or breakthrough may occur if the treatment sequence is initiated too early particularly before cycle day 1. If this occurs, the dose of Utrogestan capsules can be reduced and taken at bedtime from day 1 to day 26 of each therapeutic cycle.
Acne, urticaria, rashes, fluid retention, weight changes, gastro-intestinal disturbances, changes in libido, breast discomfort, premenstrual symptoms, menstrual disturbances; also chloasma, depression, pyrexia, insomnia, alopecia, hirsutism; rarely jaundice. Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism is more frequent among hormone replacement therapy users than among non-users.
After vaginal administration, local irritation may occur (due to the presence of soya lecithin, sunflower oil).
The following effect have been reported with soft capsules administered via the oral route.
Common undesirable effects: Altered menstrual cycles, amenorrhea, intermenstrual bleeding, headaches.
Uncommon undesirable effects: Drowsiness, transient dizziness, cholestatic jaundice, pruritus, gastrointestinal disorder.
If the treatment sequence is started too early in the month, particularly before the 15th day of the cycle, the cycle may be shortened or intercurrent bleeding may occur.
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 of the medicinal product.

Utrogestan capsules may interfere with the effects of bromocriptine and may raise the plasma concentration of cyclosporine.
Utrogestan capsules may affect the results of laboratory tests of hepatic and/or endocrine functions.
Metabolism of Utrogestan capsules is accelerated by rifamycin an antibacterial agent.
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.

Store in below 30°C and dry place, protect from light.
Shelf-life: 36 months from manufacturing date.

Oestrogens, Progesterones & Related Synthetic Drugs

G03DA04 - progesterone ; Belongs to the class of pregnen (4) derivative progestogens.

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