Progynova

Progynova

Manufacturer:

Bayer HealthCare Pharma

Distributor:

DKSH
Full Prescribing Info
Contents
Estradiol valerate.
Action
Pharmacology: Estradiol valerate, an estrogen, is a prodrug of the natural human 17β-estradiol.
Ovulation is not inhibited during the use of Progynova, and the endogenous production of hormones is hardly affected.
During the climacteric, the reduction and finally loss of ovarian estradiol secretion can result in instability of thermoregulation, causing hot flushes associated with sleep disturbance and excessive sweating, and urogenital atrophy with symptoms of vaginal dryness, dyspareunia and urinary incontinence. Less specific but often mentioned as part of the climacteric syndrome are symptoms eg, anginal complaints, palpitations, irritability, nervousness, lack of energy and concentration abilities, forgetfulness, loss of libido, and joint and muscle pain. Hormone replacement therapy (HRT) alleviates many of these symptoms of estradiol deficiency in the menopausal woman.
HRT with an adequate estrogen dosage like in Progynova reduces bone resorption and retards or halts postmenopausal bone loss. When HRT is discontinued, bone mass declines at a rate comparable to that in the immediate postmenopausal period. There is no evidence that HRT restores bone mass to premenopausal levels. HRT also has a positive effect on skin collagen content and skin thickness and can retard the process of skin wrinkling.
In recent years, many published studies have suggested that there may be a cause-effect relationship between postmenopausal oral HRT and a decrease in cardiovascular disease in women. A causal relationship between HRT and reduction of cardiovascular disease in postmenopausal women has not yet been proven. Furthermore, the effect of added progestogens on this putative benefit is unknown.
Unfavorable effects on lipid and nonlipid cardiovascular risk factors may contribute to the increased incidence of cardiovascular disease seen in women in the postmenopause. HRT changes the lipid profile. It lowers total cholesterol and LDL-cholesterol and may increase HDL-cholesterol and triglyceride levels. The metabolic effects may be counteracted to some extent by the addition of a progestogen. In general, the metabolic effects of HRT are considered beneficial and contributing to the assumed risk reduction of cardiovascular disease in postmenopausal women.
The addition of a progestogen to an estrogen replacement regimen eg, Progynova for at least 10 days per cycle is recommended in women with an intact uterus. It reduces the risk of endometrial hyperplasia and the attendant risk of adenocarcinoma in these women. The addition of a progestogen to an estrogen replacement regimen has not been shown to interfere with the efficacy of estrogen for its approved indications.
Pharmacokinetics: Absorption: Estradiol valerate is rapidly and completely absorbed. The steroid ester is cleaved into estradiol and valeric acid during absorption and the first liver passage. At the same time, estradiol undergoes extensive further metabolism eg, into estrone, estriol and estrone sulfate. Only about 3% of estradiol becomes bioavailable after oral administration of estradiol valerate. Food does not affect the bioavailability of estradiol.
Distribution: Maximum concentrations of estradiol in serum of approximately 15 pg/mL (or 30 g/mL) are generally expected between 4-9 hrs after tablet intake. Within 24 hrs after tablet intake, serum levels of estradiol are expected to decline to concentrations of about 8 pg/mL (or 15 pg/mL). Estradiol binds to albumin and the sex hormone-binding globulin (SHBG). The unbound fraction of estradiol in serum is about 1-1.5% and the SHBG-bound fraction is in the range of 30-40%.
The apparent volume of distribution of estradiol after single IV administration is about 1 L/kg.
Metabolism: After the ester cleavage of the exogenously administered estradiol valerate, the metabolism of the drug follows the biotransformation pathways of endogenous estradiol. Estradiol is mainly metabolized in the liver but also extrahepatically eg, in gut, kidney, skeletal muscles and target organs. These processes involve the formation of estrone, estriol, catecholestrogens and sulfate and glucuronide conjugates of these compounds, which are all distinctly less estrogenic or even non-estrogenic.
Elimination: The total serum clearance of estradiol following single IV administration, shows high variability in the range of 10-30 mL/min/kg. A certain proportion of estradiol metabolites are excreted in the bile and undergo a so-called enterohepatic circulation. Ultimately, estradiol metabolites are mainly excreted as sulfates and glucuronides with the urine.
Steady-State Conditions: In relation to the single dose, approximately 2 times higher serum levels of estradiol are expected after multiple administration. On average, the concentration of estradiol varies between 15 (or 30 pg/mL) (minimum levels) and 30 (or 60 pg/mL) (maximum levels). Estrone, as a less estrogenic metabolite, reaches about 8 times higher concentrations in serum, estrone sulfate reaches approximately 150 times higher concentrations. After stopping the treatment, pre-treatment levels of estradiol and estrone are reached within 2-3 days.
Toxicology: Preclinical Safety Data: Carcinogenicity: The results from toxicity studies with repeated administration including tumorigenicity studies are not suggestive of a particular risk related to use in humans. However, it has to be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumors.
Embryotoxicity/Teratogenicity: Reproduction toxicological investigations with estradiol valerate gave no indications of a teratogenic potential. As no nonphysiological estradiol plasma concentrations are produced by administration of estradiol valerate, Progynova does not present a risk to the fetus.
Mutagenicity: In vitro and in vivo studies with 17β-estradiol gave no indications of a mutagenic potential.
Indications/Uses
Hormone replacement therapy (HRT) for the treatment of signs and symptoms of estrogen deficiency due to natural menopause or castration.
Prevention of postmenopausal osteoporosis.
Dosage/Direction for Use
Adults (Including the Elderly): 1 tab daily.
If the patient has an intact uterus and is still menstruating, a combination regimen with Progynova and a progestogen should begin within the first 5 days of menstruation. If, however, the menstrual periods are very infrequent or the patient is postmenopausal, the patient may start at any time, provided pregnancy has been excluded.
Administration: Each pack covers 28 days of treatment. Treatment is continuous, which means that the next pack follows immediately without a break.
Combination Regimen: In women with intact uterus, the concomitant use of an appropriate progestogen is advised for 10-14 days every 4 weeks (sequentially combined HRT) or with each tablet of estrogen (continuous combined HRT).
Adequate provision should be made by the physician to facilitate and assure a proper compliance of the patient with the recommended combined regimen.
The tablets are to be swallowed whole with some liquid.
It does not matter at what time of the day the patient takes the tablet, but once the patient has selected a particular time, the patient should keep to it everyday. If the patient forgets to take a tablet at the usual time, it should be taken within the following 12-24 hrs. If the treatment is discontinued for a longer period of time, irregular bleeding may occur.
Overdosage
Acute toxicity studies did not indicate a risk of acute adverse effects in case of inadvertent intake of a multiple of the daily therapeutic dose.
Contraindications
HRT should not be started in the presence of any of the conditions listed as follows. Should any of the conditions appear during HRT use, Progynova should be stopped immediately.
Pregnancy and lactation; undiagnosed vaginal bleeding; known or suspected cancer of the breast; known or suspected premalignant conditions or malignancies, if sex steroid-influenced; presence or history of liver tumors (benign or malignant); severe hepatic disease; active deep venous thrombosis, thromboembolic disorders, or a documented history of these conditions; severe hypertriglyceridemia; and known hypersensitivity to any of the components of Progynova.
Special Precautions
If any of the conditions/risk factors mentioned as follows is present or deteriorates, an individual risk-benefit analysis should be done before HRT is started or continued.
Venous Thromboembolism: Epidemiological studies have suggested that HRT may be associated with an increased relative risk of developing venous thromboembolism (VTE) ie, deep venous thrombosis or pulmonary embolism. Risk/benefit should therefore be carefully weighed in consultation with the patient when prescribing HRT to women with a risk factor for VTE.
Generally recognized risk factors for VTE include a personal history, a family history (the occurrence of VTE in a direct relative at a relatively early age may indicate genetic disposition) and severe obesity. The risk of VTE also increases with age. There is no consensus about the possible role of varicose veins in VTE.
The risk of VTE may be temporarily increased with prolonged immobilization, major elective or post-traumatic surgery, or major trauma. Depending on the nature of the event and the duration of the immobilization, consideration should be given to a temporary discontinuation of HRT.
Treatment should be stopped at once if there are symptoms of a thrombotic event or suspicion thereof.
Endometrial Cancer: Prolonged exposure to unopposed estrogens increases the risk of development of endometrial hyperplasia or carcinoma. Studies have suggested that the addition of progestogens to the regimen reduces the risk of endometrial hyperplasia and cancer.
Breast Cancer: A meta-analysis from 51 epidemiological studies reported that there is a modest increase in the risk of having breast cancer diagnosed in women who have used HRT for >5 years. The findings may be due to an earlier diagnosis, the biological effects of HRT, or a combination of both. The relative risk increases with duration of treatment (by 2.3%/year of use). This is comparable to the increased risk of breast cancer observed in women with every year of delay of natural menopause (2.8%/year of delay). The increased risk gradually disappears during the course of the first 5 years after cessation of HRT. Breast cancers found in women using HRT are more likely to be localized to the breast than those found in non-users.
Liver Tumor: In rare cases, benign and even more rarely, malignant liver tumors have been observed after the use of hormonal substances eg, the one contained in Progynova. In isolated cases, these tumors led to life-threatening intra-abdominal hemorrhage. A hepatic tumor should be considered in the differential diagnosis, if upper abdominal pain, enlarged liver or signs of intra-abdominal hemorrhage occur.
Gallbladder Disease: Estrogens are known to increase the lithogenicity of the bile. Some women are predisposed to gallbladder disease during estrogen therapy.
Other Conditions: Treatment should be stopped at once if migrainous or frequent and unusually severe headaches occur for the first time, or if there are other symptoms that are possible premonitory signs of cerebrovascular occlusion.
A general association between HRT use and development of clinical hypertension has not been established. Small increases in blood pressure have been reported in women taking HRT, clinically relevant increases are rare. However, if in individual cases, a sustained clinically significant hypertension develops during the use of HRT, then withdrawing the HRT may be considered.
Nonsevere disturbances of liver function, including hyperbilirubinemias eg, Dubin-Johnson syndrome or Rotor syndrome, need close supervision and liver function should be checked periodically. In case of deterioration of markers of liver function, use of HRT should be stopped.
Recurrence of cholestatic jaundice or cholestatic pruritus which occurred first during pregnancy or previous use of sex steroids necessitates the immediate discontinuation of HRT.
Women with moderately elevated levels of triglycerides need special surveillance. HRT in these women may be associated with a further increase of triglyceride levels bearing the risk of acute pancreatitis.
Although HRT may have an effect on peripheral insulin resistance and glucose tolerance, there is generally no need to alter the therapeutic regimen in diabetics using HRT. However, diabetic women should be carefully monitored while taking HRT.
Certain patients may develop undesirable manifestations of estrogenic stimulation under HRT eg, abnormal uterine bleeding. Frequent or persistent abnormal uterine bleeding during treatment is an indication for endometrial assessment.
Uterine myomas may increase in size under the influence of estrogens. If this is observed, treatment should be discontinued.
Should endometriosis be reactivated under treatment, discontinuation of therapy is recommended.
Should there be a suspicion of a prolactinoma, this should be ruled out before starting treatment.
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking HRT.
The following conditions have been reported to occur or deteriorate with HRT use. Although the evidence of an association with HRT use is inconclusive, women with these conditions and treated with HRT should be carefully monitored: Epilepsy, benign breast disease, asthma, migraine, porphyria, otosclerosis and systemic lupus erythematosus.
Medical Examination/Consultation: A complete medical history should be taken and a physical examination should be conducted prior to the initiation or reinstitution of HRT, guided by the contraindications and warnings and should be repeated periodically. The frequency and nature of these examinations should be based on established practice guidelines and be adapted to the individual woman, but should generally include pelvic organs, including routine cervical cytology, abdomen, breasts and blood pressure.
Effects on the Ability to Drive or Operate Machinery: No adverse effects.
Use in pregnancy & lactation: HRT is not indicated for use during pregnancy or lactation.
Extensive epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used sex hormones prior to pregnancy, nor a teratogenic effect when sex hormones were taken inadvertently during early pregnancy.
Small amounts of sex hormones may be excreted in human milk.
Use In Pregnancy & Lactation
HRT is not indicated for use during pregnancy or lactation.
Extensive epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used sex hormones prior to pregnancy, nor a teratogenic effect when sex hormones were taken inadvertently during early pregnancy.
Small amounts of sex hormones may be excreted in human milk.
Adverse Reactions
In addition to the adverse effects listed under Precautions, the following undesirable effects have been reported in users of different oral HRT preparations:
Reproductive System and Breast Disorders: Changes in vaginal bleeding pattern and abnormal bleeding or flow, breakthrough bleeding, spotting, (bleeding irregularities usually subside during continued treatment), dysmenorrhea, changes of vaginal secretion, premenstrual-like syndrome, breast pain, tenderness or enlargement.
Gastrointestinal Disorders: Dyspepsia, bloating, nausea, vomiting and abdominal pain.
Skin and Subcutaneous Tissue Disorders: Rashes and various skin disorders (including pruritus, eczema, urticaria, acne, hirsutism, hair loss, erythema nodosum).
Nervous System Disorders: Headache, migraine, dizziness, anxiety/depressive symptoms and fatigue.
Miscellaneous: Palpitations, edema, muscle cramps, changes in body weight, increased appetite, changes in libido, visual disturbances, intolerance to contact lenses and hypersensitivity reaction.
Drug Interactions
Hormonal contraception should be stopped when HRT is started and the patient should be advised to take nonhormonal contraceptive precautions, if required.
Drugs: Long-term treatment with hepatic enzyme-inducing drugs (eg, several anticonvulsants and antimicrobials) can increase the clearance of sex hormones and may reduce clinical efficacy. Such hepatic enzyme-inducing properties have been established for hydantoins, barbiturates, primidone, carbamazepine and rifampicin, and are also suspected for oxcarbazepine, topiramate, felbamate and griseofulvin. Maximal enzyme induction is generally not seen before 2-3 weeks but may then be sustained for at least 4 weeks after the cessation of drug therapy.
In rare cases, reduced estradiol levels have been observed under the simultaneous use of certain antibiotics (eg, penicillins and tetracycline).
Substances which undergo substantial conjugation (eg, paracetamol) may increase the bioavailability of estradiol by competitive inhibition of the conjugation system during absorption.
In individual cases, the requirement for oral antidiabetics or insulin can change as a result of the effect on glucose tolerance.
Alcohol: Acute alcohol ingestion during use of HRT may lead to elevations in circulating estradiol levels.
Laboratory Tests: The use of sex steroids may influence biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins eg, corticosteroid-binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis.
Incompatibilities: None
Storage
Shelf-Life: 5 years.
ATC Classification
G03CA03 - estradiol ; Belongs to the class of natural and semisynthetic estrogens used in estrogenic hormone preparations.
Presentation/Packing
Tab 1 mg (sugar-coated, beige) x 3 x 28's. 2 mg (sugar-coated, blue) x 3 x 28's.
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