Active ingredients: Estradiol (estradiol valerate)
PROGYNOVA 2 mg coated tablets
Indications Why is Progynova used? What is it for?
Progynova is a medicine used in hormone replacement therapy (HRT). Progynova contains estrogen (estradiol valerate), a female sex hormone that belongs to the hormone replacement therapy (HRT) group of drugs.
This medicine is used to treat symptoms associated with postmenopause.
During menopause, the amount of estrogen produced by a woman decreases. This can lead to symptoms such as hot flashes, sweating fits, insomnia, depressive states, headaches, dizziness. Progynova relieves these postmenopausal symptoms. In addition, it can attenuate the manifestations of atrophy of the skin and mucous membranes (especially of the urogenital tract).
This medicine will only be prescribed to you if your symptoms severely hamper your daily activities.
Contraindications When Progynova should not be used
Do not take Progynova
- If you are allergic to estradiol valerate or any of the other ingredients of this medicine
- If you are pregnant or breastfeeding;
- If you have, have ever had or are suspected of having breast cancer;
- If you have had or suspect that you have a malignant tumor whose growth is sensitive to estrogen, for example a tumor of the endometrium (lining of the womb);
- If you have, or have had in the past, blood clots in the arteries or veins of the legs, in the lungs or in other parts of the body (emboli);
- If you have a high risk of blood clots forming in the vein or artery (venous or arterial thrombosis);
- If you have high levels of triglycerides (fatty substances) in your blood;
- If you have or have ever had liver tumors (benign or malignant);
- If you have angina (severe chest pain) or if you have had a myocardial infarction or stroke;
- If you have had severe liver disease and your liver function is still abnormal;
- If you have severe liver disease.
- If you have vaginal bleeding of an undetermined nature;
- If you suffer from untreated endometrial hyperplasia (thickening of the lining of the womb);
- If you have porphyria (an inherited metabolic disease due to an "alteration in the metabolism of blood pigments);
- If you have blood clotting disorders (e.g. Protein C, Protein S, or antithrombin deficiency).
If any of these conditions appear for the first time while using Progynova, stop treatment immediately and consult your doctor.
Precautions for use What you need to know before you take Progynova
Talk to your doctor or pharmacist before taking Progynova.
Your doctor will recommend whether or not you should use hormone replacement therapy (HRT). In the treatment of postmenopausal symptoms, HRT is started only for symptoms that impair quality of life. In any case, a careful evaluation of the risks and benefits of treatment should be performed at least annually, continuing HRT only as long as the expected benefits outweigh the risks.
There are limited data on the risks associated with HRT in the treatment of early menopause. However, in view of the low level of absolute risk in younger women, the risk / benefit ratio for these women may be more favorable than for older women. Before starting HRT, your doctor will ask you about your personal and family medical history. Your doctor may have your breasts and / or pelvis (lower abdomen) checked and a gynecological examination.
Your doctor will evaluate the benefits and risks of Progynova. It will check, for example, if you have a particularly high risk of developing thrombosis, due to the combination of multiple risk factors or the presence of a very serious risk factor. If there are multiple risk factors, the overall risk may be higher than the simple sum of the individual risks. If the risk is too high, your doctor will not prescribe HRT.
Once HRT has started, periodic medical check-ups (at least once a year) will still need to be carried out for an accurate assessment of the risks and benefits of continuing therapy.
- Undergo mammography screening and vaginal cytology at regular intervals.
- Regularly check for any changes in your breasts such as small depressions in the skin, changes in the nipple, or any hardening that is visible or noticeable.
If you have or have had in the past any of the following conditions, or it got worse during pregnancy or during previous hormone treatment, your doctor may check you more frequently:
- uterine fibroids or endometriosis (presence of uterine mucosa in abnormal locations);
- risk factors for thromboembolic disease (see "Thrombosis");
- risk factors for estrogen-dependent cancers (eg breast cancer in the mother);
- hypertension (high blood pressure);
- liver disease, for example a liver adenoma (benign liver tumor);
- diabetes;
- gallbladder stones;
- migraine (pain localized to one half of the head) or severe headache;
- systemic lupus erythematosus (autoimmune disease);
- history of endometrial hyperplasia (increase in the volume of mucous tissue due to an abnormal increase in the number of cells in the lining of the uterus);
- epilepsy (disease leading to seizures);
- asthma;
- otosclerosis (hereditary middle ear disease);
- benign breast pathologies;
- chorea minor (disease characterized by incoordinated involuntary movements);
- if you have hereditary angioedema, products containing estrogen can induce or aggravate the symptoms of angioedema. If you notice symptoms of angioedema such as swelling of the face, tongue and / or pharynx and / or difficulty swallowing or hives (itching and small spots on the skin) with difficulty in breathing, tell your doctor immediately.
- if you have an adenoma (benign tumor) of the anterior pituitary lobe, you will need to be followed closely by your doctor, who will prescribe periodic measurements of your prolactin levels.
If you notice a change in any of the above conditions while taking Progynova tell your doctor.
Stop treatment with Progynova immediately and contact your doctor in case of:
- jaundice (yellowing of the skin and whites of the eyes) or deterioration of liver function;
- marked increase in blood pressure;
- new onset migraine-type headache;
- pregnancy;
- symptoms or suspicion of a thrombotic event.
Effects on the cardiovascular system
Heart disease
HRT is not recommended in women who are suffering or have recently suffered from heart disease. If you have had heart disease, please tell your doctor, who will consider starting HRT. HRT has no preventive effect on heart disease.
Studies with HRT containing conjugated estrogens and medroxyprogesterone acetate as a progestogen have shown a possible increased risk of heart disease during the first year of treatment.
For other types of HRT, the risk is likely to be similar, although not yet proven.
Tell your doctor immediately if you experience chest pain which may radiate to your arm or neck, stopping use of the medicine until your doctor allows you to continue. Such pain can be a symptom of severe heart disease.
Ischemic stroke
Recent research suggests a small increased risk of ischemic stroke in association with the use of HRT. Other factors that may increase the risk of stroke include:
- old age;
- high blood pressure;
- smoke;
- excessive alcohol consumption;
- irregular heartbeat.
Tell your doctor if any of the above apply to you or if you have had a stroke in the past, so that he or she may consider starting HRT. Tell your doctor immediately if you get an unusual migraine-type headache, with or without disturbed vision by stopping use of the medicine until your doctor allows you to continue. Migraine-like headaches can be an early symptom of stroke.
Thrombosis (formation of blood clots)
HRT may increase the risk of blood clots (clots) forming inside the veins (also referred to as deep vein thrombosis or DVT), especially during the first year of treatment. These blood clots are generally not dangerous but if they break off and travel to the lungs, they can cause chest pain, difficulty breathing, collapse and even death.This condition is referred to as pulmonary embolism or PE.
Deep vein thrombosis and pulmonary embolism are examples of a condition known as venous thromboembolism or VTE.
You are at risk for thrombus formation:
- if you are of advanced age;
- if you are overweight;
- if you have had blood clots in the past;
- if one of your parents has suffered from thrombosis;
- if you have bleeding problems that require treatment with anticoagulants (medicines such as warfarin);
- if you have to be immobilized for a long time due to major surgery, trauma or illness;
- if you are pregnant or postpartum;
- if you suffer from systemic lupus erythematosus (autoimmune disease);
- if you have cancer.
Tell your doctor if you have any of the conditions listed above, so they can consider starting HRT.
Tell your doctor immediately if you experience swelling and pain in your lower limbs (swollen legs), sudden chest pain or difficulty in breathing, and stop using the medicine until your doctor authorizes you to continue. These disorders can be symptoms of a thromboembolism
Tell your doctor if you are going to have major surgery.
HRT will be stopped 4 to 6 weeks before surgery to reduce the risk of thrombosis. Your doctor will advise you on resuming HRT.
Effects on cancer risk
Breast cancer (breast cancer)
Women who have or have had breast cancer should not take HRT (see 'Do not use Progynova'). Taking HRT, as well as late menopause, slightly increases the risk of breast cancer.
The risk to a postmenopausal woman who has taken estrogen-only HRT for 5 years is equivalent to that of a woman of the same age not yet through the menopause and who has not taken HRT.
The risk for a woman taking combined estrogen / progestogen HRT is higher than for women taking estrogen alone (but the estrogen / progestogen combination has benefits for the endometrium, see "Endometrial hyperplasia and cancer").
For all HRT, the additional risk of breast cancer occurs within a few years of initiation of therapy and increases with duration of use, but returns to baseline within approximately 5 years after discontinuation of treatment. The risk of breast cancer also increases:
- if you have a close relative (mother, sister or grandmother) who has had breast cancer;
- if you are overweight.
HRT can change the appearance of mammography images (increase their density), making it more difficult in some cases to detect breast cancer. For this reason, your doctor may use other screening methods.
Contact your doctor as soon as possible if you experience any breast changes, such as small skin depressions, changes in the nipple, or any visible or noticeable hardening.
Endometrial hyperplasia and carcinoma (cancer of the lining of the uterus)
In women with an intact uterus, taking estrogen-only HRT for a long time may increase the risk of endometrial cancer.
The risk of endometrial cancer among estrogen-only users increases 2 to 12-fold compared to non-users, depending on the duration of treatment and the dose of estrogen, and may remain elevated for at least 10 years after discontinuation of treatment.
Taking a progestogen in addition to estrogen substantially reduces the additional risk of endometrial cancer.
If the uterus is still present, your doctor will prescribe a progestogen to be combined with an estrogen or combined estrogen-progestagen HRT.
If the uterus has been removed (with hysterectomy), your doctor will discuss with you the advisability of taking only the estrogen without associating the progestin.
If the uterus has been partially removed due to endometriosis (presence of uterine lining in abnormal locations), any remaining endometrial remnants may be at risk. Your doctor will then discuss with you the appropriateness of taking estrogen-progestagen HRT.
The appearance of breakthrough bleeding or spotting (small breakthrough bleeding), especially during the first courses of treatment, should not worry you.
Talk to your doctor if breakthrough bleeding or spotting continues to occur after the first months of treatment, appears after a few months of treatment or persists after stopping treatment: these symptoms could indicate a thickening of the endometrium.
Ovarian cancer
Ovarian cancer (cancer of the ovaries) is a very rare but serious condition.
Diagnosis is difficult because clear symptoms are often not present.
Some studies indicate that taking estrogen-only HRT for more than 5 years increases the risk of ovarian cancer and suggest that long-term combined HRT may confer a similar or slightly lower risk.
Hepatic (liver) tumors
After the use of hormonal substances such as those contained in Progynova, benign liver tumors have been observed in rare cases, and even more rarely malignant liver tumors. In isolated cases, these tumors lead to intra-abdominal haemorrhage which can be life-threatening. these events are extremely unlikely, you should tell your doctor if you experience any unusual abdominal pain that does not go away in a short time.
Other conditions
- If you have a tendency to develop facial blemishes (chloasma), you should minimize your exposure to the sun or ultraviolet rays during treatment with Progynova.
- HRT does not improve cognitive function. A small increased risk of probable dementia was observed in a study of women who started combined HRT after the age of 65.
- Some women are particularly prone to gallstone formation during estrogen therapy.
- Abnormal uterine bleeding may occur.
Interactions Which drugs or foods can modify the effect of Progynova
Tell your doctor if you are taking, have recently taken or might take any other medicines.
In particular, tell your doctor if you are taking:
- anticonvulsant medicines (eg phenobarbital, phenytoin, carbamazepine, oxcarbazepine, topiramate, felbamate);
- anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz, penicillins and tetracyclines);
- ritonavir, nelfinavir (medicines for AIDS);
- griseofulvin (medicine against fungal infections);
- preparations containing St. John's wort (Hypericum perforatum), used mainly for the treatment of depressive states.
These medicines may reduce the effectiveness of Progynova.
If you have diabetes, your doctor may change your treatment regimen.
The use of HRT can affect the results of some laboratory tests.
Progynova with alcohol
Excessive alcohol intake while using this medicine may affect therapy.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.
Pregnancy
Progynova is contraindicated in pregnancy. If you are or suspect that you are pregnant, do not take this medicine. If you become pregnant during treatment, stop this medicine immediately.
Feeding time
Progynova is contraindicated during breastfeeding.
Driving and using machines
No studies on the effects of this medicine on the ability to drive or use machines have been performed.
Progynova contains lactose and sucrose
If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking this medicinal product.
Dose, Method and Time of Administration How to use Progynova: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor.
Each pack covers 20 days of treatment. Take one Progynova tablet per day.
If you are still menstruating, start taking Progynova by the 5th day of your period.
In all other cases, your doctor may advise you to start treatment immediately.
If you still have your uterus (if you have not had a hysterectomy) your doctor will prescribe another hormone (progestogen) and tell you how to take it. Your doctor will also advise you whether you should take the tablets continuously (without interruption) or with a break.
It does not matter what time of day you take your tablet, but once you have set a certain time, you should try to take your tablets at the same time all the time. The tablet can be swallowed with a small amount of liquid.
Follow the instructions for use carefully, otherwise you will not fully benefit from treatment with Progynova.
Use in children and adolescents
Progynova is not indicated for use in children and adolescents
Use in the elderly
There are no data indicating the need for dosage adjustment in elderly patients. Tell your doctor if you are over 65 (see "Warnings and precautions").
Use in patients with impaired hepatic (liver) function
No formal studies have been conducted in patients with hepatic impairment. Progynova is contraindicated in women with severe liver disease (see "Do not take Progynova").
Use in patients with impaired renal (kidney) function
No formal studies have been conducted in patients with impaired renal function.
Overdose What to do if you have taken too much Progynova
If you take more Progynova than you should
There are no reports of adverse effects from overdose, which therefore generally does not require treatment. There are no specific antidotes and treatment must cure the symptoms. Based on the experiences made with other hormonal preparations, it has been observed that overdose can cause nausea, vomiting and vaginal bleeding.
If you have taken too much Progynova, contact your doctor or pharmacist immediately.
If you forget to take Progynova
If you have forgotten to take a tablet, take it as soon as possible. Take the next tablet at the usual time. Do not take a double dose to make up for a forgotten tablet. If it has been more than 24 hours, do not take any additional tablets. Failure to take one or more tablets may increase the likelihood of breakthrough bleeding and spotting.
If you stop using Progynova
If you stop taking Progynova, menopausal symptoms due to estrogen deficiency may return.
Side Effects What are the side effects of Progynova
Like all medicines, this medicine can cause side effects, although not everybody gets them. These effects generally disappear after the first months of treatment and can be divided as follows:
Common side effects (may affect up to 1 in 100 women):
- weight gain / loss,
- headache (headache),
- abdominal pain (stomach ache),
- nausea,
- rash,
- itch,
- uterine / vaginal bleeding, including spotting (small intermenstrual discharge).
Uncommon side effects (may affect up to 1 in 1,000 women):
- hypersensitivity reaction (allergy),
- depressed mood,
- dizziness,
- visual disturbances,
- palpitations,
- dyspepsia (difficult digestion),
- erythema nodosum (disease characterized by red nodules under the skin, located in the legs and feet, more rarely in the forearms), hives (skin rash resembling irritation from nettle, accompanied by a sense of burning and itching),
- breast pain and breast tenderness,
- edema (swelling).
Rare side effects (may affect up to 1 in 10,000 women):
- anxiety,
- increased / decreased libido (sexual desire),
- migraine (pain localized to one half of the head),
- contact lens intolerance,
- flatulence (presence of gas in the intestine),
- He retched,
- hirsutism (increased hair growth),
- acne,
- muscle cramps,
- dysmenorrhea (painful menstruation),
- vaginal discharge,
- symptoms mimicking PMS,
- breast enlargement,
- fatigue.
In women with hereditary angioedema, exogenous estrogens can induce or aggravate the symptoms of angioedema (see "Warnings and precautions").
An increased risk has been observed for the following conditions in women who use HRT compared to non-users:
- breast cancer
- cancer of the lining of the uterus (endometrium)
- ovarian cancer
- clots in a vein in the legs or lungs (venous thromboembolism)
- heart disease
- ischemic stroke For more information about these side effects, see the section "Warnings and precautions".
Other side effects that have been reported with the use of estrogen-progestins:
- myocardial infarction;
- diseases of the gallbladder;
- effects on the skin: chloasma (skin lesion consisting of brown patches of irregular shape and of variable size usually located on the face, neck, chest and back of the hands), erythema multiforme (inflammation of the skin manifesting itself as reddish patches), erythema nodosum (red and hard nodules of the skin), vascular purpura (pinpoint hemorrhages of the skin and mucous membranes);
- probable dementia over 65 years of age.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects you can help provide more information on safety. of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children
Do not use this medicine after the expiry date which is stated on the package after EXP. The expiry date refers to the last day of that month.
This medicinal product does not require any special storage conditions.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Progynova contains
- The active substance is estradiol valerate. Each tablet contains 2.0 mg of estradiol valerate
- The other ingredients are: lactose monohydrate, maize starch, povidone 25, talc, magnesium stearate, sucrose, povidone 90, macrogol 6,000, calcium carbonate, wax E, glycerol 85%, titanium dioxide, indigo carmine.
Description of what Progynova looks like and contents of the pack
Progynova comes in the form of coated tablets, in packs of 20 tablets
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
PROGYNOVA 2 MG COATED TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each coated tablet contains 2 mg estradiol valerate.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Coated tablet.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Hormone replacement therapy (HRT) for symptoms resulting from estrogen deficiency in postmenopausal women.
04.2 Posology and method of administration
Method of administration
Oral use.
Progynova is an estrogen-only medicine.
For the treatment of postmenopausal symptoms, the lowest effective dose should be used; HRT should only be continued as long as the benefit obtained in relieving severe symptoms outweighs the risk.
• How to start Progynova
Hysterectomised patients can start treatment at any time.
In patients with an intact uterus and a menstrual cycle present, start a combined regimen of Progynova and a progestogen (see under "Combination regimen") by the 5th day of menstruation.
Patients with amenorrhea, sporadic or postmenopausal menstrual cycles can start a combination regimen (see under "Combination regimen") at any time after excluding pregnancy.
Switching from other HRTs (cyclic, continuous sequential or continuous combined)
Women who are using other HRTs must complete their current course of therapy before starting Progynova therapy.
• Dosage
One tablet a day.
• Administration
Treatment with estrogen alone
Each pack covers 20 days of treatment. After each 20-day cycle, there may be a break in taking the tablets, usually a week or less (cyclic HRT), or the tablets may be taken continuously every day (continuous HRT). once a package is finished, another must be started.
Combination regimen (estrogen + progestin)
In women with an intact uterus, concomitant use of an appropriate progestogen is recommended usually for 12-14 days during each 4-week cycle (sequential continuous HRT or cyclic HRT) or every day with each estrogen tablet without interruption (continuous HRT). combined).
The doctor should advise on how to start treatment, for patients starting treatment for the first time or for patients who change their type of HRT (cyclic, sequential or continuous combined).
The physician must do everything possible to facilitate and ensure adequate adherence of the patient to the prescribed combination regimen.
The tablets should be taken whole with some liquid and preferably always at the same time of day.
Unless there is a previous diagnosis of endometriosis, the addition of a progestogen is not recommended in women without a uterus.
• Forgotten tablets
If a tablet is forgotten, it should be taken as soon as possible. If more than 24 hours have passed, no additional tablets should be taken.
Missing one or more doses may increase the likelihood of breakthrough bleeding and spotting.
Additional information for particular categories of patients
Children and adolescents
Progynova is not indicated for use in children and adolescents
Elderly patients
There are no data indicating the need for dosage adjustment in elderly patients. For women over the age of 65, see section 4.4.
Patients with impaired hepatic function
No formal studies have been conducted in patients with hepatic impairment. Progynova is contraindicated in women with severe liver disease (see section 4.3).
Patients with impaired renal function
No formal studies have been conducted in patients with renal impairment (see section 4.4).
04.3 Contraindications
HRT should not be initiated in any of the situations listed below. If any of these conditions appear during HRT use, stop treatment immediately.
• Hypersensitivity to the active substance or to any of the excipients
• Pregnancy and lactation (see section 4.6)
• Past, suspected or known breast cancer
• Undiagnosed genital bleeding
• Known or suspected malignant tumors or estrogen-dependent precancerous states (eg endometrial cancer)
• Previous or present liver tumors (benign or malignant)
• Severe hypertriglyceridaemia
• Untreated endometrial hyperplasia
• Current or previous venous thromboembolism (eg deep vein thrombosis, pulmonary embolism)
• Known thrombophilic disorders (eg Protein C, Protein S, or antithrombin deficiency, see section 4.4)
• High risk of venous or arterial thrombosis
• Active or recent arterial thromboembolic disease (eg angina pectoris, myocardial infarction, stroke)
• Severe liver disease
• Acute or past liver disease until liver function values have returned to normal
• Porphyria
04.4 Special warnings and appropriate precautions for use
When treating postmenopausal symptoms, HRT should only be started for symptoms that impair quality of life. In any case, a careful evaluation of the risks and benefits of treatment should be performed at least once a year, continuing HRT only as long as the expected benefits outweigh the risks.
There are limited data on the risks associated with HRT in the treatment of early menopause. However, in view of the low level of absolute risk in younger women, the risk / benefit ratio for these women may be more favorable than for older women.
Medical examination and subsequent checks
Before initiating or restarting HRT, a complete family and personal medical history should be taken by the physician. A general and gynecological examination (including pelvic and breast examination) guided by medical history and contraindications should also be performed and warnings for use.
During treatment, periodic clinical checks of a nature and frequency appropriate to the individual case are recommended. Women should be educated about breast changes they should report to their doctor or nurse (see "Breast cancer" below). Clinical investigations, including the use of appropriate diagnostic imaging tools, such as mammography, should be performed in line with currently accepted clinical protocols and the clinical needs of the individual case.
Conditions that require special control
If any of the following conditions is present, or has been present in the past, and / or has been aggravated by pregnancy or previous hormone treatment, the patient should be followed closely. Please note that these conditions may recur or worsen during treatment with Progynova:
• Leiomyoma (uterine fibroids) or endometriosis
• Risk factors for thromboembolic disease (see below)
• Risk factors for estrogen-dependent cancers (eg first degree heredity for breast cancer)
• Hypertension
• Liver diseases (eg liver adenoma)
• Diabetes mellitus with or without vascular involvement
• Cholelithiasis
• Migraine or headache (severe)
• Systemic lupus erythematosus
• History of endometrial hyperplasia (see below)
• Epilepsy
• Bronchial asthma
• Otosclerosis
• Benign mastopathy
• Korea minor
Indications for an "immediate suspension of treatment
Treatment must be suspended immediately if the existence of a contraindication is highlighted and in the following cases:
• Jaundice or deterioration of liver function, or recurrence of cholestatic itching or jaundice that first occurred during pregnancy or previous use of sex steroids.
• Significant increase in blood pressure.
• New onset migraine-like headache, particularly frequent or intense headaches or other possible prodromal symptoms of cerebrovascular occlusion
• Pregnancy.
• Symptoms or suspicion of a thrombotic event.
In the event that the conditions or risk factors listed below present or worsen, the individual benefit-risk ratio should be re-evaluated, taking into consideration the possibility of discontinuing therapy.
The possibility of a synergistic increase in the risk of thrombosis in women who have a combination of risk factors or in whom a single risk factor is present with particular severity should be considered. This increased risk may be greater than the simple sum of the percentages of risk attributable to individual factors HRT should not be prescribed in case of negative benefit / risk assessment.
Tumors
Endometrial hyperplasia and carcinoma
In women with an intact uterus, the risk of endometrial hyperplasia and carcinoma is increased following administration of estrogen alone for long periods. The risk of endometrial cancer among estrogen-only users increases 2 to 12-fold compared to non-users, depending on the duration of treatment and the dose of estrogen (see section 4.8). Upon cessation of treatment, the risk may remain elevated for at least 10 years.
In non-hysterectomised women, cyclical addition of a progestogen for at least 12 days per month / 28 day cycle, or combined estrogen-progestogen therapy, prevents the increased risk associated with estrogen-only HRT.
For oral doses of estradiol greater than 2 mg, conjugated equine estrogens (EEC) greater than 0.625 mg, and transdermal patches releasing estrogen doses greater than 50 mcg / day, the endometrial safety of adding a progestogen has not been demonstrated.
Breakthrough bleeding and spotting may occur during the first months of treatment. If these episodes appear after some time from the start of therapy, or continue after the suspension of treatment, the causes of these phenomena must be investigated, including by endometrial biopsy to rule out a malignant tumor of the endometrium.
Unbalanced estrogen stimulation can lead to premalignant or malignant transformation of residual foci of endometriosis. The addition of progestogens to estrogen-only HRT is therefore recommended in women who have undergone hysterectomy for endometriosis if they have known residual endometriosis.
Breast cancer
Overall evidence suggests an increased risk of breast cancer in women taking estrogen-progestogen, and possibly estrogen-only HRT, which depends on how long they take HRT.
Estrogen-progestogen combination therapy
The Women's Health Initiative (WHI) randomized placebo-controlled study and epidemiological studies are in agreement in detecting an increased risk of breast cancer in women taking estrogen-progestogen HRT, which occurs after approximately 3 years of use (see section 4.8 ).
Estrogen-only therapy
The WHI study did not find an increased risk of breast cancer in hysterectomised women taking estrogen-only HRT. Most observational studies have reported a modest increased risk of having breast cancer diagnosed, which is substantially lower than that seen in users of estrogen-progestogen combinations (see section 4.8).
The increased risk occurs after a few years of treatment, but returns to baseline within a few (at most five) years after discontinuation of treatment.
Estimates of the overall relative risk of breast cancer diagnoses calculated across more than 50 epidemiological studies appear to be between 1 and 2 in most studies. The relative risk increases with duration of treatment and may be lower or indifferent with drug-based products of estrogen only.
In the two randomized trials with CEE, alone or in continuous combination with MPA, a risk of 0.77 (95% CI: 0.59-1.01) or 1.24 (95% CI: 1.01) was estimated -1.54) after 6 years of HRT. It is not known whether the increased risk also applies to other products used for HRT.
Many studies have reported that cancers diagnosed in current or recent HRT users tend to be better differentiated than those found in non-users. Data relating to out-of-breast spread are not conclusive.
Hormone replacement therapy, especially estrogen-progestogen combinations, increases the density of mammographic images, which can make radiological detection of a breast cancer more difficult.
Ovarian cancer
Ovarian cancer is much rarer than breast cancer. Long-term (at least 5-10 years) HRT with estrogen alone has been associated with a slightly increased risk of ovarian cancer (see section 4.8). Some studies, including the WHI study, suggest that long-term HRT with combination products may confer a similar or slightly lower risk (see section 4.8).
Liver tumors
Benign liver tumors and even more rarely malignant liver tumors have been observed in rare cases after the use of hormonal substances such as those contained in Progynova. In isolated cases, these tumors cause life-threatening intra-abdominal haemorrhage.
Venous thromboembolism
HRT is associated with a 1.3 to 3-fold risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. These events are more likely to occur in the first year of HRT than in subsequent years (see section 4.8).
Patients with a history of venous thromboembolism or known thrombophilic states have an increased risk of VTE and HRT may increase this risk. HRT is therefore contraindicated in such patients.
In the absence of a "personal history of VTE, women with a first degree relative with a history of thrombosis at a young age may be offered to undergo screening, after having been informed of its limitations (screening allows to identify only a part of the defects If a thrombophilic defect is identified that segregates with thrombosis in a family member, or if the defect is 'severe' (e.g. antithrombin, protein S, protein C deficiency, or a combination of defects) HRT is contraindicated.
Women already being treated with anticoagulants require careful assessment of the benefit-risk ratio of HRT.
Generally recognized risk factors for VTE include, use of estrogen, major surgery, prolonged immobilization, a personal or family history (a "history of VTE in a first degree relative at a relatively early age may indicate a genetic predisposition)," obesity severe (BMI> 30 kg / m2), pregnancy, / postpartum period, systemic lupus erythematosus (SLE) and cancer. The risk of VTE also increases with age. There is no consensus on the possible role of varicose veins in venous thromboembolism.
As in all operated patients, scrupulous attention must be paid to prophylactic measures to prevent episodes of postoperative venous thromboembolism. When prolonged immobilization is anticipated following elective surgery, temporary discontinuation of HRT 4 to 6 weeks prior to surgery is recommended. Treatment should not be resumed until after complete mobilization of the woman.
The risk of venous thromboembolism may be temporarily increased in cases of prolonged immobilization, major elective or post-traumatic surgery, or severe trauma. Depending on the nature of the event and the duration of the immobilization, a temporary suspension of HRT should be considered.
When prescribing HRT to a woman with a risk factor for VTE, the risk / benefit ratio should be carefully weighed with the patient.
If VTE develops after initiation of therapy, the drug should be discontinued. Patients should be advised to contact their physician immediately in case of symptoms potentially due to venous thromboembolism (eg swollen and painful lower limb, sudden pain thoracic, dyspnoea).
Coronary artery disease
Randomized controlled trials show no protection against myocardial infarction in women with or without coronary artery disease who have received estrogen-progestogen or estrogen-only HRT.
Estrogen-progestogen combination therapy
The relative risk of coronary artery disease during estrogen-progestogen HRT use is slightly increased. As the baseline absolute risk is largely age-dependent, the number of additional cases of coronary artery disease due to estrogen-progestogen use is very large. small in healthy women recently in menopause, but increases in later life.
Estrogen-only therapy
Randomized controlled trials have not shown an increased risk of coronary artery disease in hysterectomised women using estrogen-only therapy.
Ischemic stroke
Estrogen-progestogen or estrogen-only therapies are associated with a 1.5-fold increased risk of ischemic stroke. The relative risk does not change with age or the time since menopause. However, as the baseline absolute risk is largely age-dependent, the overall risk of stroke in women who use HRT will increase with age. advancing age (see section 4.8).
Cholecystopathy
Estrogen increases the lithogenicity of bile. Some women are predisposed to cholecystopathy during estrogen therapy.
Other conditions
• Since the intake of estrogen may lead to fluid retention, patients with impaired renal or cardiac function should be monitored. Patients with end stage renal insufficiency should be monitored closely, as increased blood pressure can be expected. blood concentration of the active ingredient of Progynova.
• An association between the use of HRT and the onset of hypertension has not been confirmed. Modest increases in blood pressure have been reported in women taking HRT, but clinically significant increases are rare. However, if clinically significant hypertension develops in individual cases during HRT use, discontinuation of therapy should be considered.
• Non-serious disorders of liver function, including hyperbilirubinaemia such as Dubin-Johnson syndrome or Rotor syndrome, require close monitoring and periodic monitoring of liver function. In the event of worsening of liver function indices, hormone replacement therapy should be discontinued.
• Women with pre-existing hypertriglyceridaemia should be followed closely during estrogen therapy or HRT, as rare cases of major increases in plasma triglycerides and subsequent pancreatitis following estrogen therapy have been reported in this condition.
• Estrogen increases the levels of TBG, the globulin that binds thyroid hormones, resulting in an increase in total circulating thyroid hormones measured as PBI (protein bound iodine), T4 (column method or RIA) or T3 (RIA method). Resin uptake of T3 is reduced to reflect the increase in TBG. Free fractions of T4 and T3 are unchanged. Other binding proteins, such as corticoglobulin (CBG) and sex hormone binding globulin (SHBG), may be increased and lead to an increase in circulating levels of corticosteroids and sex steroids respectively. Free or biologically active hormone fractions are unchanged. Other plasma proteins may also be increased (angiotensinogen / renin substrate, alpha-1-antitrypsin, ceruloplasmin).
• HRT does not improve cognitive function. There is evidence of an increased risk of probable dementia in women who start using combination or estrogen-only therapy after age 65. It is not known whether these findings also apply to younger postmenopausal women or to other hormone replacement therapy products.
• Although HRT may have an effect on peripheral insulin resistance and glucose tolerance, there is no need to change the treatment regimen in diabetic women using HRT. However, women with diabetes should be closely monitored while taking it. of the TOS.
• During HRT, some patients may develop unwanted manifestations of estrogen stimulation, such as abnormal uterine bleeding. Frequent or persistent abnormal uterine bleeding during treatment is an indication for an evaluation of the endometrium. If, despite the treatment, menstrual irregularities persist, the presence of organic pathologies must be excluded by resorting to suitable diagnostic techniques.
• Uterine fibroids (myomas) can increase in size under the influence of estrogen. In this case, treatment should be stopped.
• If, during treatment, a reactivation of endometriosis is observed, it is recommended that therapy be discontinued.
• If the patient has prolactinoma, close medical attention is required (including periodic measurement of prolactin levels).
• 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 while taking HRT.
• In women with hereditary angioedema, exogenous estrogens can induce or aggravate the symptoms of angioedema.
Information about some of the ingredients of Progynova
The medicine contains lactose, therefore patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
The medicine contains sucrose, therefore patients with rare hereditary problems of fructose intolerance and sucrase isomaltase insufficiency should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
Estrogen metabolism may be enhanced by the concomitant use of substances known to induce drug-metabolizing enzymes, particularly cytochrome P450, such as anticonvulsants (eg phenobarbital, phenytoin, carbamazepine) and anti-infectives (rifampicin , rifabutin, nevirapine, efavirenz).
Oxcarbazepine, topiramate, felbamate and griseofulvin are also potential inducers of liver enzymes. Maximal enzyme induction is generally not observed for 2-3 weeks but may last for at least 4 weeks after discontinuation of therapy.
In rare cases, reduced estradiol levels have been observed with concomitant use of some antibiotics (eg, penicillins and tetracyclines).
Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones.
Herbal preparations such as Hypericum perforatum can induce estrogen metabolism.
Increased estrogen metabolism may result in reduced clinical effects and changes in the uterine bleeding profile.
Substances that undergo substantial conjugation (eg paracetamol) can increase the bioavailability of estradiol by competitive inhibition of the conjugation system during absorption.
In individual cases, the need for oral antidiabetic drugs or insulin may change as a result of the effect of HRT on glucose tolerance.
• Interaction with alcohol
Acute alcohol ingestion during HRT use can lead to increased circulating levels of estradiol.
• Interaction with laboratory tests
The use of sex steroids can influence biochemical parameters relating to, for example, liver, thyroid, adrenal and renal function, plasma levels of (transporter) proteins such as globulin that binds corticosteroids and lipid / lipoprotein fractions, parameters of metabolism glucose and the parameters of coagulation and fibrinolysis.
04.6 Pregnancy and lactation
Pregnancy
Progynova is contraindicated in pregnancy (see section 4.3). If pregnancy occurs during treatment with Progynova, treatment should be stopped immediately.
The results of most of the epidemiological studies available indicate that accidental exposure of the fetus to estrogen does not cause teratogenic or foetotoxic effects.
Feeding time
Progynova is contraindicated during breastfeeding. Small amounts of sex hormones may be excreted in breast milk.
04.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive or use machines have been performed.
04.8 Undesirable effects
Serious side effects associated with hormone replacement therapy are also reported in section 4.4 (Special warnings and precautions for use).
The table below lists the undesirable effects reported in women using HRT, classified by MedDRA system organ (MedDRA SOCs).
The most appropriate MedDRA term was used to describe a specific adverse reaction, its synonyms and related conditions.
In women with hereditary angioedema, exogenous estrogens can induce or aggravate symptoms of angioedema (see section 4.4).
Breast cancer risk
• An increased risk of having breast cancer diagnosed is reported in women taking estrogen-progestogen therapy for more than 5 years, which can be doubled.
• The increased risk in users of estrogen-only therapies is significantly lower than that observed in users of estrogen-progestogen combinations.
• The level of risk depends on the duration of use (see section 4.4).
• Results from the placebo-controlled study (WHI study) and the larger epidemiological study (MWS) are shown below.
Million Women Study - Additional Risk valued breast cancer after 5 years of use
US WHI Studies - Additional risk of breast cancer after 5 years of use
‡ When the analysis was restricted to women who had not used HRT prior to the study there was no increased risk during the first 5 years of treatment: after 5 years the risk was higher than in non-users.
** WHI study in women with no uterus, which did not show an increased risk of breast cancer.
Endometrial cancer risk
Postmenopausal women with the uterus
The risk of endometrial cancer is approximately 5 in 1000 women with a uterus who are not using HRT.
In women with a uterus, the use of estrogen-only HRT is not recommended as it increases the risk of endometrial cancer (see section 4.4).
Depending on the duration of use and the dose of estrogen, the increased risk of endometrial cancer in epidemiological studies varies between 5 and 55 additional cases per 1000 women between 50 and 65 years.
Adding a progestogen to estrogen-only therapy for at least 12 days per cycle may prevent this increased risk. In the Million Women Study, the use of estrogen-progestogen HRT (sequential or combined) did not increase the risk of endometrial cancer (RR 1.0 (0.8-1.2)).
Ovarian cancer
Long-term use of estrogen-only or estrogen-progestogen HRT was associated with a small increased risk of ovarian cancer. In the Million Women Study, 5 years of HRT resulted in 1 additional case per 2500 users.
Risk of venous thromboembolism
HRT is associated with a 1.3 to 3-fold increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. These events are more likely to occur during the first year of use (see section 4.4). The results of the WHI studies are shown below:
WHI Studies - Additional risk of VTE after 5 years of use
§ WHI study in women without a uterus
Risk of coronary heart disease
• The risk of coronary artery disease is slightly increased in users of estrogen-progestogen HRT over the age of 60 (see section 4.4).
Risk of ischemic stroke
• The use of estrogen-only or estrogen-progestogen therapies is associated with an increased relative risk of ischemic stroke of up to 1.5. The risk of haemorrhagic stroke does not increase during HRT use.
• This relative risk is independent of age or duration of use. However, as the baseline risk is highly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see section 4.4).
WHI studies combined - Additional risk of ischemic stroke§ after 5 years of use
§ No distinction was made between ischemic and haemorrhagic stroke.
Other undesirable effects have been reported with the use of estrogen-progestogens:
• cholecystopathies;
• skin and subcutaneous tissue disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura;
• probable dementia over the age of 65 (see section 4.4).
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous 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. "address www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
Acute toxicity studies do not indicate risks of acute side effects after accidental intake of a dose even many times higher than the therapeutic one. Some women may experience nausea, vomiting and withdrawal bleeding.
There is no specific antidote and treatment should be symptomatic.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: sex hormones and modulators of the genital system, estrogens.
ATC code: G03CA03.
The active ingredient, synthetic 17β-estradiol, is chemically and biologically identical to endogenous human estradiol. It compensates for the loss of estrogen production in postmenopausal women and relieves menopausal symptoms.
• Reduction of estrogen deficiency symptoms
Relief of menopausal symptoms is achieved during the first few weeks of treatment.
05.2 Pharmacokinetic properties
After oral administration, estradiol valerate is rapidly and completely absorbed. The ester of the steroid is broken down into estradiol and valeric acid during absorption and the first hepatic pass. It reaches its maximum plasma peak 1-3 hours after administration. estradiol levels remain elevated for 24 hours.
Following repeated daily dosing, no increase in plasma estradiol occurs.
The excretion for the most part occurs in the form of metabolites: 90% in the urine and 10% via the faecal route.
The half-life of estradiol excretion is 1 day.
05.3 Preclinical safety data
The toxicological profile of estradiol is well known. There are no preclinical data relevant to the prescriber in addition to those already mentioned in other sections.
• Carcinogenicity
The results of repeated dose toxicity studies, including studies on carcinogenic potential, do not suggest special risks related to use in humans. However, it should be noted that sex hormones can promote the growth of certain hormone-dependent tissues and tumors.
• Embryotoxicity / teratogenicity
Reproductive toxicity studies with estradiol valerate have not yielded indications of a teratogenic potential. Since administration of estradiol valerate does not result in non-physiological plasma concentrations of estradiol, this preparation does not present a risk to the fetus.
• Mutagenicity
Studies in vitro And in vivo with 17b-estradiol they gave no indication of a mutagenic potential.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Lactose monohydrate, corn starch, povidone 25, talc, magnesium stearate, sucrose, povidone 90, macrogol 6,000, calcium carbonate, wax E, glycerol 85%, titanium dioxide, indigo carmine.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
5 years.
06.4 Special precautions for storage
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
PVC / Aluminum blister containing 20 coated tablets.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Bayer S.p.A. Viale Certosa, 130 - 20156 Milan
08.0 MARKETING AUTHORIZATION NUMBER
A.I.C. n. 021226016
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
04.04.1969/01.06.2010
10.0 DATE OF REVISION OF THE TEXT
10/2015
