Source: Marketing Authorisation Holder Revision Year: 2023 Publisher: Bayer Israel LTD, 36 Hacharash st., Hod Hasharon 4527702 Manufacturer: Bayer Weimar GMBH UND CO.KG, Dobereinerstrasse 20, Weimar 99427, Germany
Every hormone replacement therapy (HRT) must be preceded by a clinical check on general health and a thorough gynecological examination, and the latter should be repeated at least once a year. The patient’s own and her family’s medical history should also be taken into account. The risk-benefit ratio must be carefully weighed up for each patient prior to the start of therapy and should be reviewed regularly during treatment. The lowest possible dosage and the shortest possible duration of treatment should always be selected.
Before starting treatment, pregnancy should be excluded. If withdrawal bleeding fails to occur at about 28-day intervals, the possibility of pregnancy should be considered in perimenopausal women.
If any of the above contraindications should occur during HRT therapy or in any of the following situations, treatment must be discontinued immediately:
If the following complaints exist, have recently occurred and/or have deteriorated during a pregnancy or during a previous hormone treatment, the patient should be monitored carefully. It should be taken into consideration that these complaints may recur or worsen during treatment with Progyluton:
If any of the following conditions or risk factors apply for the first time or are exacerbated, the individual risk/benefit analysis must be reviewed, terminating therapy if necessary.
Randomized controlled studies and epidemiological investigations showed an enhanced risk of developing breast cancer among women who were given HRT for several years. Prior to the start of HRT all women must therefore undergo breast examination by a doctor, and selfexaminations of the breast should be performed once a month. The users should be informed of which breast changes they must report to their doctor. Depending on the age and the respective risk factors, mammography may be indicated in addition.
A meta analysis of 51 epidemiological studies revealed that the risk of contracting breast cancer increases with the duration of HRT and decreases after discontinuation of HRT. The relative risk (RR) of contracting breast cancer was 1.35 (95% confidence interval (CI) 1.21-1.49) among women receiving HRT for 5 years or longer.
The Women’s Health Initiative (WHI) study, a large, prospective, placebo-controlled, randomized study of more than 8,000 elderly, postmenopausal women (age at the start of the study 50-79, mean age 63), showed that, in comparison to placebo under combined HRT with conjugated estrogens and medroxyprogesterone acetate (MPA) after an average administration period of 5.6 years, there was an increase in invasive breast cancer in the estrogen/progestogen group (RR 1.24 [95% CI 1.02-1.50]). It is not known whether there is a similar risk for other combined HRT preparations. For the estrogen monotherapy, on the other hand, there was no enhanced risk (RR 0.77 [95% CI 0.59-1.01]).
The Million Women Study, a nonrandomized cohort study, recruited 1,084,110 women. The average age of the women on entering the study was 55.9 years. Half of the women received HRT before and/or at the beginning of the study, the other half had never been given HRT. 9,364 cases of invasive breast cancer and 637 deaths due to breast cancer were recorded after an average observation period of 2.6 and 4.1 years, respectively. Women who were using HRT at the beginning of the study demonstrated, in comparison with the women who had never received such a therapy, a higher morbidity risk (RR 1.66 [95% CI 1.58-1.75]) and possibly, but less pronounced, a higher mortality from breast cancer (RR 1.22 [95% CI 1.00-1.48]). The highest risk was seen in the combined estrogen/progestogen therapy group (RR 2.00 [95% CI 1.88-2.12]). The relative risk was 1.30 (95% CI 1.21-1.40) for the estrogen monotherapy. The results were similar for the different estrogens and progestogens, for the various doses and administration routes and for continuous and sequential therapy. With all the types of HRT the risk increased with the duration of administration. After discontinuation of therapy the risk receded (last use more than 5 years previously): RR 1.04 [95% CI 0.95-1.12]).
HRT increases opacity in mammographic images, and this can impair the radiological detection of breast cancer in some cases.
Prolonged administration of estrogen increases the risk of developing endometrial hyperplasia or a carcinoma. Studies suggest that this increased risk is largely minimized by the additional administration of a progestogen.
Medical monitoring is necessary for all women who use an HRT. All cases of abnormal bleeding (irregular, heavy or persistent bleeding, including spotting) must be investigated by means of appropriate diagnostic techniques (if applicable, including a histological investigation of the endometrium) in order to rule out an organic cause or a malignant finding.
Several epidemiological studies suggest that HRT may be associated with an enhanced risk of developing epithelial ovarian carcinoma. An increased risk was found both for estrogen monotherapy and for combined HRT. While most studies revealed an increased risk only after long-term use (i.e. at least 5 years), no such relationship with the duration of administration was found in a meta-analysis published in 2015 (taking into consideration a total of 17 prospective and 35 retrospective studies).
In the prospective, randomized, placebo-controlled WHI study, a statistically nonsignificant increased risk was found (HR 1.41; 95% CI 0.75-2.66).
Since ovarian carcinoma occurs much more rarely than breast cancer, the absolute increased risk is low in women who are using or have recently used an HRT.
In rare cases after the use of hormonal active ingredients such as those that are contained in Progyluton, benign changes, and even more rarely malignant changes, in the liver have been observed, which in isolated cases led to life-threatening hemorrhages in the abdominal cavity. For this reason a hepatic tumor should be included in differential diagnosis considerations, if severe upper abdominal pain, liver engorgement or signs of an intraabdominal hemorrhage occur.
HRT should not be employed to prevent cardiovascular diseases.
Major clinical studies failed to show any positive effect in the primary prophylaxis (WHI study) or secondary prophylaxis (HERS study) of cardiovascular diseases.
The WHI study showed, in postmenopausal women who received an oral HRT with conjugated estrogens and MPA for an average of 5.2 years, an increased risk of cardiovascular events compared with placebo (RR 1.24 [95% CI 1.00-1.54], absolute increase in the risk = 6 cases per 10,000 women years). The risk was highest in the first year of HRT (RR 1.81 [95% CI 1.09-3.01]). The risk increased with the length of time since the menopause (menopause <10 years: RR 0.89; menopause 10-19 years: RR 1.22; menopause ≥20 years: RR 1.71).
Likewise, the cerebrovascular risk in the WHI study was seen to be enhanced in the combined estrogen/progestogen therapy cohort (RR 1.31 [95% CI 1.02-1.68]).
In the estrogen/monotherapy arm of the WHI study no significant effect on the cardiovascular risk was detected (RR 0.91 [95% CI 0.75-1.12]). On the other hand, the risk for cerebrovascular insults was enhanced (RR 1.39 [95% CI 1.10-1.77]).
The Heart and Estrogen/Progestin Replacement Study (HERS and HERS II), a prospective, placebo-controlled, randomized study, showed in more than 1,300 postmenopausal women with preexisting coronary heart condition (mean age at inclusion in study 67 years), who received an oral HRT with conjugated estrogens and MPA for an average of 4.1 years (HERS) and 2.7 years (HERS II), no reduction in the cardiovascular risk. The relative risk was 0.99 (95% CI 0.84-1.17). The risk was highest in the first year of HRT (RR 1.52 [95% CI 1.01-2.29]).
Only limited data is available on HRT with the therapy starting at a relatively young age (for example, before the age of 55). This data suggests that the increase in the cardiovascular risk while undergoing HRT could be less in younger patients who have gone through menopause more recently than in the population (which tended to be older) investigated in the abovementioned studies. However, this is not the case for cerebrovascular events.
The relative risk for cerebrovascular events is independent of age or the time since menopause. However, since the basic risk of a stroke depends strongly on age, the overall risk increases with advancing age for women undergoing HRT.
Alternative therapies should be considered for women already possessing risk factors for the development of cardiovascular or cerebrovascular events.
HRT is associated with an enhanced risk for VTE, (e.g. deep vein thrombosis, pulmonary embolism).
Two controlled randomized studies (HERS and WHI) and several epidemiological studies revealed a 2-3-fold risk increase among women on HRT as compared with women who had never received such therapy. In particular, the WHI study demonstrated an enhanced incidence of pulmonary embolisms. The absolute rise in risk among women on HRT was 8 cases in 10,000 women years (15 as against 7), the relative risk being 2.13 (95% CI 1.39-3.25).
The heightened risk was only found in women currently on HRT and not among women who had had HRT in the past. The risk appears to be higher in the first few years of administration.
Even in the estrogen monotherapy arm of the WHI study, the risk of venous thromboembolism tended to increase. The relative risk of deep venous thrombosis was 1.47 (95% CI 0.87-2.47), and that of a pulmonary embolism was 1.34 (95% CI 0.70-2.55).
Among nonusers the number of VTE cases over a period of 5 years within the age group of 50-59 years was estimated to be 3 out of 1,000 women and in the age group of 60-69 years 8 out of 1,000 women. Among healthy women who take HRT for 5 years an additional 2-6 cases per 1,000 women occur among the age group 50-59 and 5-15 additional cases in the 60-69 year age bracket.
If corresponding symptoms or a suspected VTE occurs, the preparation must be discontinued immediately. Patients with risk factors for thromboembolic events should be closely monitored. In such women the risk-benefit ratio must be weighed up carefully and, if possible, other therapies should be considered.
The known risk factors for the occurrence of VTE include a corresponding medical history of the patient or her family’s medical history (the occurrence of VTE in a close relative at a relatively young age may point to a genetic disposition), smoking, significant excess weight, systemic lupus erythematosus and malignant diseases.
Considering women with a combination of risk factors or a more highly pronounced single risk factors, it should be taken into account that the risk may be superadditive. This may possibly result in a contraindication for HRT.
The risk of venous thromboembolic events occurring may be temporarily enhanced during prolonged immobilization, major surgery or after a serious accident. In women undergoing hormone replacement, the greatest attention must be paid to preventive measures in order to avoid venous thromboembolisms after surgery. Depending on the type of surgery and duration of immobilization, thought should be given to a temporary break in HRT treatment, in the case of elective surgery possibly several weeks (4-6 weeks) in advance. Treatment should only be resumed when the women is completely mobile again.
In the Women’s Health Initiative Memory Study (WHIMS), a randomized, placebo-controlled study subordinated to the WHI study, more than 2,000 women aged above 65 years (average age 71) received oral conjugated equine estrogens and medroxyprogesterone acetate and were monitored over an average period of 4 years.
In addition, 1,464 hysterectomized women aged between 65 and 79 were treated with oral conjugated equine estrogens alone and were monitored for an average of 5.2 years. Neither treatment with conjugated estrogens and medroxyprogesterone acetate nor with estrogen monotherapy showed any positive effect on cognitive function. The risk of any cerebral disturbance occurring (probably dementia) was actually higher (RR 2.05 [95% Cl 1.21-3.48] for the combined HRT. In absolute numbers this means an additional 23 cases per year per 10,000 women being treated.
Although it is still unclear to what extent the results of these studies may be extrapolated to a younger population or to HRT preparations with different active ingredients they should be taken into account by the doctor when judging the risk/benefit ratio of HRT.
Estrogens may cause fluid retention. Patients with conditions that may worsen as a result (such as heart or kidney function disorders, asthma, epilepsy or migraine) should therefore be monitored carefully.
An HRT may lead to an increase in triglyceride levels, which may increase the risk of pancreatitis in patients with preexisting hypertriglyceridemia. Therefore, the triglyceride levels should be monitored in such patients.
No clear association has been recorded to date between the use of HRT and the development of clinical hypertension. A slight increase in blood pressure has been seen in women on HRT, but a clinically significant increase is rare. If a continually enhanced blood pressure is ascertained under HRT, consideration should be given to the idea of discontinuing treatment.
Patients who take hypotensive medication at the same time as Progyluton should have their blood pressure checked on a regular basis.
Women with liver function disorders, including hyperbilirubinemia, such as Dubin-Johnson syndrome or rotor syndrome, must be monitored carefully, and the liver parameters must be checked. If the liver values worsen, the HRT should be discontinued.
After viral hepatitis has subsided, approximately 6 months should pass before preparations such as Progyluton are administered.
Estrogens can enhance lithogenicity in the gallbladder. As a result, the risk of gallbladder diseases (particularly cholelithiasis) is increased in some women undergoing estrogen therapy.
Clinical studies have demonstrated an influence of HRT on peripheral insulin resistance and glucose tolerance. As a rule, however, it is not necessary to make any adjustments to antidiabetic therapy. Diabetics on HRT should have their blood sugar levels closely monitored.
It is necessary for patients with a preexisting prolactinoma to be monitored closely by the doctor (this includes regular prolactin level determinations), since it has been reported that in isolated cases prolactinomas have increased in size under estrogen therapy.
Renally impaired patients or those with metabolic bone diseases accompanied by hypercalcemia should, as with any estrogen-containing preparation, only use Progyluton after a careful weighing up of the benefits and risks.
As a result of estrogen stimulation, some patients on HRT may suffer undesired side effects, such as unusually heavy bleeding. Frequent and persistent irregular bleeding is a sign of endometrial activity and must be clarified by appropriate diagnostic means in order to rule out organic diseases.
Uterine myomas may increase in size under estrogen therapy. If this is detected, therapy should be discontinued.
Should an endometriosis be reactivated under HRT it is recommended to discontinue this therapy.
On occasions, chloasma may occur, particularly in women with a history of chloasma gravidarum. Women with a predisposition for chloasma should not expose themselves to the sun or other ultraviolet radiation during HRT.
In women with hereditary angioedema, any exogenous estrogens may trigger or exacerbate the symptoms of angioedema.
Progyluton has no contraceptive effect. If necessary, nonhormonal contraceptive methods should be used.
Each Progyluton white coated tablet contains 46.220 mg lactose monohydrate. Each Progyluton light brown coated tablets contain 45.720mg lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption who are following a lactose-free diet should bear this quantity in mind.
In order to detect potential interactions, the summary of product characteristics of the concomitantly administered medicinal products should also be consulted.
An enhanced clearance of sex hormones owing to the induction of hepatic enzymes may lead to reduced plasma concentrations of estrogens and/or progestogens and thus impair the clinical efficacy as well as possibly cause bleeding irregularities. The same is true, for example, for barbiturates, bosentan, carbamazepine, felbamate, modafinil, oxcarbazepine, phenytoin, primidone, rifabutin, rifampicin and topiramate, as well as for medicinal products that contain St. John’s wort (Hypericum perforatum). Enzyme induction can already be observed after a few days and can last for at least 4 or more weeks after discontinuation of these medicinal products. Maximum enzyme induction generally appears after a few weeks.
Strong and moderate CYP3A4 inhibitors such as azole antimycotics (e.g. itraconazole, voriconazole, fluconazole), macrolide antibiotics (e.g. clarithromycin, erythromycin), diltiazem, verapamil and grapefruit juice can increase the plasma concentrations of estrogens and/or progestogens or both.
Several inhibitors of HIV/HCV protease and of non-nucleoside reverse transcriptase can raise or lower the plasma concentrations of estrogen or progestogens if they are administered concomitantly with an HRT. These changes may be clinically relevant in some cases.
In the case of concomitant short-term (up to 10 days) administration of antibiotics that do not exhibit any interactions with the CYP3A4 enzyme system, pharmacokinetic interactions are not expected. There is insufficient data available concerning possible interactions during longer-term comedication with antibiotics (e.g. for borreliosis or osteomyelitis). Reduction of the active substance levels due to an influence on the enterohepatic circulation cannot be ruled out here.
Sex hormones may also influence the pharmacokinetics of other medicinal products. Correspondingly, their plasma concentrations can be either increased (e.g. ciclosporin) or reduced (e.g. lamotrigine, see below).
An interaction study with lamotrigine, which is an antiepileptic, and a combined oral contraceptive (30 µg ethinylestradiol/150 µg levonorgestrel) revealed a clinically relevant increase in lamotrigine clearance with a corresponding significant decrease in the lamotrigine plasma level when these medicinal products were administered concomitantly. Such a decrease in the plasma concentrations may be accompanied by reduced seizure control. Adjustment of the lamotrigine dose may be necessary.
Other hormonal contraceptives and HRT have not been investigated. However, it is expected that such preparations have a comparable interaction potential. If treatment with Progyluton is initiated in a patient who is taking lamotrigine, an adaptation of the lamotrigine dose may therefore be necessary, and the lamotrigine concentrations should be closely monitored at the beginning of the therapy.
Upon discontinuation of Progyluton, the lamotrigine levels may increase again, and so the patient should also be monitored in this phase and if necessary the lamotrigine dose should be reduced.
Sex hormones may also influence the effect of oral anticoagulants.
In clinical studies where combined contraceptives containing ethinylestradiol were administered concomitantly with specific combinations (ombitasvir/paritaprevir/ritonavir used in the therapy of HCV infections with or without dasabuvir, glecaprevir/pibrentasvir; sofosbuvir/velpatasvir/voxilaprevir), a clinically relevant increase in ALT (including cases of an increase to more than five times the upper limit of the normal range) occurred significantly more frequently compared with patients who were treated exclusively with the antiviral active substances. During administration of other estrogens (especially estradiol and estradiol valerate), on the other hand, the incidence of a transaminase elevation was not greater than in patients without estrogen therapy. Due to the limited number of women who were taking such other estrogen-containing medicinal products, however, caution is absolutely advised in the case of concomitant administration of estrogens with any of the above drug combinations.
The use of Progyluton is contraindicated during pregnancy. If pregnancy occurs or is suspected during its use, the drug must be discontinued immediately.
There are, on the strength of animal experiments, signs of risks to the fetus. Most of the epidemiological studies conducted to date have failed to show any conclusive evidence of an embryotoxic or teratogenic effect, if estrogens or combinations of estrogens and progestogens were administered inadvertently during pregnancy.
During lactation, there is no indication for Progyluton.
The medicinal product must not be used during lactation, since milk production is reduced and the quality of the milk may change; also low concentrations of the substance can be detected in the milk.
No studies have carried out in this respect. Progyluton is not expected to influence the ability to drive or operate machines, cf. however the section “Undesirable effects”.
The serious undesirable effects linked to the use of an HRT are also described in the section “Special warnings and special precautions for use” (q.v.).
The following lists the undesirable effects by organ system and frequency, observed under HRT preparations. A connection with Progyluton cannot be corroborated, nor can it be ruled out.
The frequency brackets are defined as follows: common ≥1/100 and <1/10; uncommon ≥1/1,000 and <1/100; rare ≥1/10,000 and <1/1,000); unknown (based predominantly on spontaneous reports from post-market surveillance, exact frequency cannot be estimated)
Uncommon: mammary carcinoma.
Unknown: endometrial carcinoma.
Uncommon: hypersensitivity reactions.
Common: weight gain.
Unknown: weight loss.
Common: mood swings, depression.
Uncommon: changes in libido*, nervousness.
Rare: anxiety.
* Both decreased and increased libido have been reported.
Common: headache.
Uncommon: sleep disorders, dizziness, migraine.
Uncommon: visual impairments.
Uncommon: palpitations, increased blood pressure, venous and arterial thromboembolic events (e.g. deep venous thrombosis, pulmonary embolism, myocardial infarction, stroke).
Common: flatulence, stomach pain, nausea, dyspepsia.
Uncommon: vomiting.
Uncommon: abnormal liver function tests.
Very rare: cholestatic jaundice.
Unknown: cholelithiasis (and other gallbladder diseases).
Common: skin rash, pruritus.
Uncommon: acne, hirsutism, alopecia, urticaria.
Unknown: chloasma, erythema nodosum, erythema multiforme, vascular purpura.
Common: back pain.
Uncommon: muscle cramps.
Very common: feeling of tightness in the breasts, breast pain, bleeding anomalies (menorrhagia, metrorrhagia, spotting, etc.)
Common: abdominal pain, vaginal discharge, increased size of uterine myomas, enlargement of the breasts.
Rare: dysmenorrhea, premenstrual syndrome.
Unknown: endometrial hyperplasia.
Common: peripheral edema, asthenia.
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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/
None known.
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