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SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 1 soft capsule contains:
3. PHARMACEUTICAL FORM Capsule, soft
Size of the capsule: 100 mg: round 5 200 mg: oval 10
4. CLINICAL PARTICULARS 4.1 Therapeutic indications
4.2 Posology and method of administration Posology
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The recommended dose is as follows, according to the indication: In luteal failure (irregular periods): The treatment should be taken for 10 days per cycle, usually from the 17th to 26th day inclusive. The average dosage is 200 to 300 mg of progesterone per day, taken as 1 or 2 divided doses, i.e. 200 mg in the evening at bedtime plus 100 mg in the morning if required. In the treatment of menopause: oestrogen-only therapy is not recommended on its own in menopausal women with an intact uterus. A single intake of 200 mg progesterone at bedtime has to be added at least 12 to 14 days per month, i.e. in the last 2 weeks of each treatment sequence, followed by approximately one week without any replacement therapy and during which withdrawal bleeding may occur.
Paediatric population There is no relevant use of
Method of administration This product is intended for oral use only. The medicinal product should not be taken with food, preferably in the evening at bedtime. The second intake should be in the morning.
4.3 Contraindications This medicinal product must not be used in the following situations: Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Undiagnosed genital bleeding Severe liver dysfunction Liver tumours Suspected or confirmed breast or genital organ neoplasia Thromboembolic diseases, active or in the history Cerebral haemorrhage Porphyria In case of a contraindication related with estrogens when
4.4 Special warnings and precautions for use Under the recommended conditions for use, this treatment is NOT A CONTRACEPTIVE. 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 bleeding may occur.
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Patients must be monitored closely if they have a history of venous thrombosis. If uterine bleeding is present, do not prescribe before establishing a cause, particularly with endometrial investigations. Because of the metabolic risks and risks of thromboembolism which cannot be entirely excluded, administration should be discontinued in the event of: . Occular disorders such as reduced vision, diplopia and retinal vascular lesions; . Venous thromboembolic or thrombotic events, regardless of location; . Severe headaches. If the patient develops amenorrhoea during treatment, ensure that she is not pregnant.
Medical examination/follow-up 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. 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.
Endometrial hyperplasia In women with still intact endometrium, regular period-like withdrawal bleeding may occur early on in the treatment, which decreases or stops altogether with increasing atrophy of the endometrium in the course of long-term treatment. In the absence of this withdrawal bleeding, endometrial hyperplasia should be excluded by suitable measures. Breakthrough bleeding and spotting may occur during the first few months of the treatment. If break-through 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 risks of combined use of estrogens and progestogens for postmenopausal hormone therapy are described in detail in the summaries of product characteristics of the particular estrogen- containing medicinal products.
4.5 Interaction with other medicinal products and other forms of interaction Drugs known to induce the hepatic CYP450-3A4 such as barbiturates, anti-epileptic agents (phenytoin, carbamazepine), rifampicin, phenylbutazone, spironolactone, griseofulvin, some
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antibiotics (ampicillin, tetracyclines) and also herbal products containing St. John’s wort (Hypericum perforatum) may increase the elimination of progesterone. Ketoconazole and other inhibitors of CYP450-3A4 may increase bioavailability of progesterone. Progesterone may affect the results of laboratory tests of hepatic and/or endocrine functions. Progestogens may decrease glucose tolerance and thus, may increase insulin resistance or resistance to any other antidiabetic agents used in patients with diabetes mellitus.
4.6 Fertility, pregnancy and lactation Pregnancy A large amount of data on pregnant women indicate no malformative nor feto/neonatal toxicity of progesterone.
Breastfeeding There is insufficient information on the excretion of progesterone/metabolites in human milk. Secretion of progesterone into breast milk has not been studied in detail.
Fertility As this medicinal product is indicated to support luteal failure in subfertile or infertile women, there is not deleterious known effect on fertility.
4.7 Effects on ability to drive and use machines Drivers and machine operators in particular are alerted to the risks of drowsiness and/or dizziness associated with oral use of this medicinal product. These problems can be avoided by taking the capsules at bedtime.
4.8 Undesirable effects The following adverse reactions have been seen by oral route of administration: Rare System organ Common Uncommon Very rare 1/10000; class 1/100; <1/10 1/1000; ≤1/100 ≤1/10000 ≤1/1000 Menstruation Mastodynia Reproductive irregular system and Amenorrhoea breast disorders Metrorrhagia Headaches Drowsiness Depression Nervous system Fleeting dizzy disorders sensations
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Vomiting Nausea Gastrointestinal Diarrhoea disorders Constipation Hepatobiliary Cholestatic disorders jaundice Immune system Anaphylactoid Urticaria disorders reactions Skin and Pruritus Chloasma subcutaneous Acne tissue disorders
Drowsiness and/or fleeting dizzy sensations are seen particularly with concomitant hypoestrogenism. These effects disappear immediately without compromising the benefit of treatment when doses are reduced or estrogenism is increased. 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. Changes in periods, amenorrhoea or intercurrent bleeding have been observed and associated with the use of progesterone in general.
Other adverse reactions have been reported in association with estrogen/progestogen treatment used as hormone replacement therapy in postmenopausal women: - Estrogen-dependent benign or malignant tumour, e.g. endometrial carcinoma. - Venous thromboembolisms, i.e. thrombosis of the deep leg or pelvic veins as well as pulmonary embolism occur more often in users of hormone replacement therapy than in non- users. - Myocardial infarction and stroke. - Gall bladder disorders. - Skin and subcutaneous tissue disorders: chloasma, erythema multiforme, erythema nodosum, and vascular purpura. - Probable dementia.
Detailed information on the side effects of combined use of oestrogens and gestagens for postmenopausal hormone therapy are described in the summaries of product characteristics for the particular estrogen-containing medicinal products.
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 national reporting system listed in Appendix V.
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4.9 Overdose The adverse reactions described in section 4.8 are usually signs of overdose. These disappear without treatment when the dosage is reduced. The usual dosage may be excessive in some people because of persistence or recurrence of unstable endogenous progesterone secretion, particular sensitivity to the substance or excessively low concomitant blood oestradiol concentrations. In these situations: The dosage should be reduced or the progesterone should be administered AT BEDTIME IN THE EVENING, 10 days per cycle, if drowsiness or fleeting dizziness occurs. Treatment should be started later in the cycle (such as on day 19 instead of day 17) if the cycle is shortened or spotting occurs. Check that oestradiol concentrations are sufficient in the perimenopausal period and in hormone replacement therapy for the menopause.
5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Sex hormones and modulators of the genital system, progestogens, ATC code: G03DA04
5.2 Pharmacokinetic properties Absorption Micronised progesterone is absorbed in the digestive tract. Blood concentrations of progesterone rise from the first hour after dosing and the highest plasma concentrations are found 1 to 3 hours after dosing. Because of the hormone tissue retention time, the daily dosage appears to need to be divided into two separate doses 12 hours apart in order to achieve hormone exposure throughout the 24-hour period.
Distribution
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Progesterone is approximately 96%-99% bound to serum proteins, primarily to serum albumin (50%-54%) and transcortin (43%-48%).
Biotransformation The plasma and urinary metabolites are identical to those found following physiological secretion from the ovarian corpus luteum: in plasma these are mostly 20-alpha hydroxy delta-4 pregnenolone and 5-alpha dihydroprogesterone. 95% of urinary excretion is in the form of glycuronide-conjugated metabolites, the major one of which is 3 alpha-5 beta pregnanediol (pregnandiol).
Elimination Urinary elimination is observed for 95% in the form of glycuronide-conjugated metabolites, mainly 3α,5β–pregnanediol (pregnandiol).
Linearity/non-linearity The pharmacokinetics of micronized progesterone, both absorption and elimination, were independent of the dose administered and dose proportionality has been confirmed. Although there are some variations which are not clinically relevant, the same individual retains the same pharmacokinetic characteristics at several months distance. This permits appropriate individual adaptation of the posology. Pharmacokinetic/pharmacodynamic relationship A significant body of published information related to a clear pharmacokinetic/ pharmacodynamic relationship support the efficacy of natural micronised progesterone, particularly: - In menstrual irregularities and in adjunctive use with an estrogen for post-menopausal women with an intact uterus (for hormone therapy).
5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients Capsule contents: Sunflower oil soybean lecithin Capsule shell:
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Gelatin glycerol titanium dioxide (E171)
6.2 Incompatibilities Not applicable.
6.3 Shelf life 3 years
6.4 Special precautions for storage Do not store above 30°C. Do not refrigerate. Store in the original packaging in order to protect from moisture
6.5 Nature and contents of container Packs of 30 or 90 soft capsules of
6.6 Special precautions for disposal Any unused medicinal products or waste must be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER [To be completed nationally]
8. MARKETING AUTHORISATION NUMBER(S)
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
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[To be completed nationally]
10. DATE OF REVISION OF THE TEXT