UTROGESTAN 100mg capsules: Soft, round, off-white capsules containing 100mg progesterone (micronized).
Pharmacotherapeutic group: Genitourinary system and sex hormones ATC code: G03DA04 Progesterone is a natural progestogen, the main hormone of the corpus luteum and the placenta. It reacts specifically with progesterone receptor which regulates gene transcription through direct interaction with DNA. It acts on the endometrium by converting the proliferating phase to the secretory phase with predecidualization of the endometrium. Micronized progesterone has all the properties of endogenous progesterone with dose-dependent induction of a full secretory endometrium and has in particular gestagenic, antiestrogenic, slightly antiandrogenic and tranquillising effects through the interactions with the GABA receptors and antialdosterone effects.
Absorption
Micronised progesterone is absorbed by the digestive tract. Blood progesterone levels increase from the first hour and peak plasma levels are obtained 1 to 3 hours after administration. There are considerable variations between individuals after oral administration, though a same subject retains the same pharmacokinetic characteristics over a period of several months, allowing good individual dosage adjustment. The low between-individual variations in the progesterone levels after vaginal administration make it possible to precisely predict the effect obtained with a standard dosage. The mean recommended dosage induces stable, physiological plasma concentrations of progesterone, similar to those observed during the luteal phase of a normal ovulatory menstrual cycle.
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 , 5 -pregnanediol (pregnandiol).
Metabolism
Progesterone is metabolised primarily by the liver. The main plasma metabolites are 20 hydroxy- 4 - prenolone and 5 -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. The plasma 5-pregnanolone concentration is not increased after vaginal administration. Urinary elimination mainly takes place in the form of 3, 5-pregnanediol (pregnandiol) as shown by the progressive increase in its concentration (to a peak concentration of 142 ng/ml at 6 hours). UTROGESTAN - UTROGEST004 20 February 2013
- 2 -
Special populations
Hepatic Insufficiency and Renal Insufficiency:
No formal studies have evaluated the effect of hepatic disease or renal disease on the disposition of progesterone. However, since progesterone is metabolized by the liver and eliminated by the kidneys, use in patients with liver or renal dysfunction disease requires careful monitoring.
Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology and toxicity.
Adjunctive use with oestrogen in post-menopausal women with an intact uterus. (HRT)
In women receiving oestrogen replacement therapy there is an increased risk of endometrial cancer which can be countered by progesterone administration. The recommended dose is 200mg 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 100mg can be given at bedtime from day 1 to day 25 of each therapeutic cycle, withdrawal bleeding being less with this treatment schedule.
Children
Not applicable.
Elderly
As for adults.
Oral. UTROGESTAN 100mg capsules should not be taken with food.
Known allergy or hypersensitivity to progesterone or to any of the excipients. Hypersensitivity to soya. Severe hepatic dysfunction. Undiagnosed vaginal bleeding. Mammary or genital tract carcinoma. Thrombophlebitis. Thromboembolic disorders. Cerebral haemorrhage. Porphyria.
Prescription of progesterone beyond the first trimester of pregnancy has revealed rare cases of non-serious and reversible liver abnormalities (gravidic cholestasis-like). UTROGESTAN 100mg 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 100mg capsules are intended to be co-prescribed with an oestrogen 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 oestrogen product should be referred to for information about the risks of venous thromboembolism. UTROGESTAN - UTROGEST004 20 February 2013
- 3 -
There is suggestive evidence of a small increased risk of breast cancer with oestrogen 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 oestrogen 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 warnings for this product. UTROGESTAN 100mg capsules should not be taken with food and should be taken at bedtime. Concomitant food ingestion increases the bioavailability of UTROGESTAN 100mg capsules. UTROGESTAN 100mg 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. 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 screen 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.
Pregnancy
Animal data
Reproductive studies have been performed in mice at doses up to 9 times the human oral dose, in rats at doses up to 44 times the human oral dose, in rabbits at a dose of 10 mg/day delivered locally within the uterus by an implanted device, in guinea pigs at doses of approximately one-half the human oral dose and in rhesus monkeys at doses approximately the human dose, all based on body surface area, and have revealed little or no evidence of impaired fertility or harm to the foetus due to progesterone.
Human data
Several studies in women exposed to progesterone have not demonstrated any significant increase in foetal malformations. Because the studies in humans cannot rule out the possibility of harm, progesterone capsules should not be used during pregnancy unless indicated.
Lactation
Detectable amounts of progesterone enter the breast milk. The effect of this on the nursing infant has not been determined.
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. UTROGESTAN - UTROGEST004 20 February 2013
- 4 -
Clinical Trial Data
The table below lists adverse experiences which were reported in >=10% of patients (regardless of relationship to treatment) who received cyclic micronized progesterone capsules, 200mg daily (12 days per calendar month cycle) with daily conjugated oestrogen, in a multicentre, randomized, double-blind, placebo-controlled clinical trial in 875 postmenopausal women.
| Adverse experiences (>10%) reported in an 875 patient placebo-controlled trial in postmenopausal women over a 3-year period [percentage (%) of patients reporting] | |||
| Micronized capsules 200mg with conjugated oestrogens 0.625mg (N=178) | Conjugated oestrogens 0.625mg (only) (N=175) | Placebo (N=174) | |
| Gastrointestinal disorders Abdominal bloating Abdominal pain | 12 10 | 10 13 | 5 10 |
| Nervous system and psychiatric disorders Headache Depression Dizziness | 31 19 15 | 30 18 5 | 27 12 9 |
| Reproductive system and breast disorders Breast tenderness Hot flashes Vaginal discharge | 27 11 10 | 16 14 10 | 6 35 3 |
| Miscellaneous Joint pain Urinary problems | 20 11 | 22 10 | 29 9 |
Post-Marketing Experience
Gastrointestinal disorders
Very rare:nausea
Nervous system and psychiatric disorders
Very rare:somnolence, transient dizziness, malaise, may occur 1 to 3 hours after intake of the drug. In this case, it would be recommended to reduce the dosage per dose or to change the dosing schedule, take the dose at bedtime or far from a meal. Very rare:headache
Reproductive system and breast disorders
Very rare:breast tenderness, shortening of the cycle or breakthrough bleeding may occur. If this occurs, the dose of progesterone should be adapted.
Miscellaneous
Very rare:non serious and reversible liver abnormalities (gravidic cholestasis-like) mostly during pregnancy, visual disturbances, anaphylactic reactions. UTROGESTAN - UTROGEST004 20 February 2013
- 5 -
N.B. Very common:>= 1/10 (>= 10%) Common (frequent): >= 1/100 and < 1/10 (>= 1% and < 10%) Uncommon (infrequent): >= 1/1000 and < 1/100 (>= 0.01% and < 0.1%) Rare:1/10,000 and < 1/1000 (>= 0.01% and < 0.1%) Very rare:< 1/10,000 (< 0.01%)
Concomitant food ingestion increased the bioavailability of micronized progesterone capsules.
Metabolism of progesterone capsules by human liver microsomes was inhibited by ketoconazole (IC50 <0.1 M) 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. Metabolism of progesterone capsules by the liver was accelerated by hepatic inducers (e.g. barbiturates, antiepileptics, rifampycin, etc).
The following laboratory results may be modified by the use of progesterone: Levels of gonadotropines, plasma progesterone and urinary pregnanediol.
No case of overdosage has been reported with progesterone. In the case of overdosage, progesterone capsules should be discontinued and the patient should be treated symptomatically.
Capsule contents: sunflower oil, soya lecithin Capsule shell: gelatin, glycerol, titanium dioxide (E171)
None.
Store in the original package. Store below 30 C.
Prescription Medicine
Each box contains 30 units of 100mg soft capsules packed in blister strips. UTROGESTAN - UTROGEST004 20 February 2013
- 6 -
Nil.
Distributed by: Pharmaco (NZ) Ltd P O Box 4079 Auckland Ph: (09) 377 3336
20 February 2013 (CCDS version 2.0 April 2010) UTROGESTAN - UTROGEST004 20 February 2013