Utrogestan

Utrogestan 100 mg: Each capsule contains 100 mg micronised Progesterone (INN).
Utrogestan 200 mg: Each capsule contains 200 mg micronised Progesterone (INN).
Excipients/Inactive Ingredients: Sunflower oil, Soya lecithin, Gelatin, Glycerol, Titanium dioxide.

Pharmacotherapeutic group: urogenital system and sex hormones. ATC-code: G03DA04.
Pharmacology: Pharmacodynamics: Progesterone is the 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. Micronised 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 through the interactions with the GABA receptors and antialdosterone effects.
Pharmacokinetics: Progesterone has a short elimination half-life and undergoes extensive first-pass hepatic metabolism when given orally; oral bioavailability is very low although it may be increased somewhat by an oily vehicle and by micronisation. Progesterone is absorbed when given buccally, rectally, or vaginally, and rapidly absorbed from the site of an oily intramuscular injection.
Various derivatives have been produced to extend the duration of action and to improve oral activity. Esters of progesterone derivatives such as hydroxyprogesterone caproate are used intramuscularly, and megestrol acetate is orally active. The ester medroxyprogesterone acetate is used orally and parenterally. 19-Nortestosterone progestogens have good oral activity because the 17-ethinyl substituent slows hepatic metabolism.
Progesterone and the progestogens are highly protein bound; progesterone is bound to albumin and corticosteroid binding globulin; esters such as medroxyprogesterone acetate are mainly bound to albumin; and 19-nortestosterone analogues are bound to sex-steroid binding globulin and albumin. Progesterone is metabolized in the liver to various metabolites including pregnanediol, which are excreted in the urine as sulfate and glucuronide conjugates. Similarly, progestogens undergo hepatic metabolism to various conjugates, which are excreted in the urine. Progesterone is distributed into breast milk.
Pharmacokinetic parameters after administration of progesterone: According to route of administration: The comparison of the pharmacokinetics showed a significant difference for mean plasma concentrations of Area Under the Curve (AUC;ng.h/ml). Mean concentration in the steady state (CSS) and Maximum concentration (Cmax) after one factor variance analysis for four groups taken together: the test was also significant. (P<0.0001), and (P<0.05 for Tmax). (See table.)

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Toxicology: Preclinical safety data: Data not supplied.

Oral route: Disorders related to Progesterone insufficiency and in particular: Primary and secondary amenorrhea.
Premenstrual disorders.
Bleeding due to fibroma.
Adjunctive use with oestrogen in post-menopausal women.
Vaginal route: To help pregnancy, in particular: Luteal phase support during in vitro fertilisation cycles.
Threatened miscarriage or prevention of habitual miscarriage due to luteal phase deficiency up to the 12th week of pregnancy.
Preterm labour.

Posology: The recommended dosages must be strictly respected in all therapeutic indications.
Whatever the indication and route of administration (oral or vaginal), the dosage should never exceed 200 mg per intake.
Oral route: In Progesterone insufficiency the average dosage is from 200 to 300 mg micronised Progesterone per day. This medicinal product should be taken without food preferably in the evening before going to bed.
In pre-menstrual disorders, amenorrhea (primary & secondary) and bleeding due to fibroma, the usual treatment regimen is 200 to 300 mg per day: 200 mg in a single evening dose before retiring, or 300 mg in 2 dividing doses (200 mg before going to bed and 100 mg in the morning if necessary), 10 days per cycle, usually from the 17th to the 26th day inclusive.
In hormone replacement therapy in women receiving isolated estrogen there is an increased risk of endometrial cancer which should be countered by Progesterone administration.
One dose (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.
Two doses (each of 100 mg, or a single dose of 200 mg) in the evening before retiring, 12 to 14 days per month, or the last two weeks of each treatment sequence. This treatment must be followed by the total discontinuation of any replacement therapy for approximately one week during which a deprivation haemorrhage is often observed.
Vaginal route: Each capsule must be inserted deep in the vagina.
Supplementation of the luteal phase during IVF cycles: The recommended dosage is from 400 to 600 mg/day, in two to three divided doses, from the day of hCG injection up until the 12^th week of pregnancy.
Threatened miscarriage or prevention of habitual miscarriage due to luteal phase insufficiency: the recommended dosage is from 200 to 400 mg/day in two divided doses up until the 12^th week of pregnancy.
Preterm labour: Women with a history of preterm labour - 100 mg/day until 36^th week of pregnancy. Women with cervix shorter than 15 mm detected at 22-26 weeks - 200 mg daily until the 36^th week of pregnancy.

No case of overdosage was reported with Progesterone. In the case of overdosage, Progesterone capsules should be discontinued, and the patient should be treated symptomatically.

Known allergy or hypersensitivity to Progesterone or to any of the excipients. The capsules contain sunflower oil and should never be used by patients allergic to sunflower seed. Undiagnosed vaginal bleeding. Mammary or genital tract carcinoma. Thrombophlebitis. Thromboembolic disorders. Cerebral haemorrhage. Porphyria.
Increased risk of venous thromboembolism is documented with the use of oral contraceptive pill and oral HRT related to the estrogen component. No study has evaluated the effect of the progestin component alone in HRT.

Progesterone Capsules are not suitable for use as a contraceptive. In case of prescription of Progesterone beyond the first trimester of pregnancy, cases of non serious and reversible liver abnormalities (gravidic cholestasis-like) have been reported.

Prior to taking hormone (and at regular intervals thereafter) each woman should be assessed. A personal and family medical history should be taken and physical examination should include special reference to breast and pelvic organ as well as cervical cytology. Progesterone Capsules should be used cautiously in patients such as with conditions that might be aggravated by fluid retention (e.g. cardiac disease, renal disease, epilepsy, migraine, asthma); in patients with a history of depression, diabetes, mild to moderate hepatic dysfunction, migraine.
Effects on ability to drive and use machines: Progesterone Capsules may cause drowsiness and/or dizziness in a minority of patients; therefore caution is advised. Taking the capsules at bedtime should reduce these effects during the day.

Pregnancy: There have also been reports of congenital malformations, including limb reduction defects, neural tube defects, and congenital heart malformations after intra-uterine exposure to progestogen in early pregnancy. However, many analyses of accumulated data have found no evidence of a recognizable malformation syndrome.
Lactation: Detectable amounts of Progesterone enter the breast milk. The effect of this on the nursing infant has not been determined.

Progesterone and the progestogens may cause gastrointestinal disturbances, changes in appetite or weight, fluid retention, oedema, acne, chloasma (melasma) allergic skin rashes, urticarial, mental depression, breast changes including discomfort or occasionally gynaecomastia, changes in libido, hair loss, hirsutism, fatigue, drowsiness or insomnia, fever, headache, premenstrual syndrome-like symptoms, and altered menstrual cycles or irregular menstrual bleeding. Anaphylaxis or anaphylactoid reactions may occur rarely. Alterations in the serum lipid profile may occur, and rarely alterations in liver-function tests and jaundice. Pain, diarrhoea, and flatulence have followed rectal use.

Food interaction: Concomitant food ingestion increased the bioavailability of Micronised Progesterone Capsules.
Drug - Drug interaction: Metabolism of Progesterone Capsules 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. Metabolism of Progesterone Capsules by liver was accelerated by hepatic inducers (e.g. barbiturate, antiepileptics, rifampicin).
Lab tests interaction: The following laboratory results may be modified by the use of Progesterone: levels of gonadotropins, plasma Progesterone and urinary pregnanediol.

Incompatibilities: Not applicable.
Instructions for use and handling: No special requirements.

Store below 30°C.
Shelf-life: 3 years.

Oestrogens, Progesterones & Related Synthetic Drugs

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

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