Active ingredients: Estradiol
Vagifem 25 micrograms film-coated vaginal tablet
Vagifem package inserts are available for pack sizes:- Vagifem 25 micrograms film-coated vaginal tablet
- Vagifem 10 micrograms vaginal tablets
Indications Why is Vagifem used? What is it for?
VAGIFEM belongs to a group of medicines called estrogens.
It is used for the treatment of atrophic estrogen deficiency vaginitis.
Experience in women over the age of 65 is limited.
Contraindications When Vagifem should not be used
Do not use "Vagifem":
- if you have, have had or are suspected of having breast cancer
- if you have had or are suspected of having a malignant tumor whose growth is sensitive to estrogen, for example in the endometrium (lining of the womb)
- if you have or have been treated in the past for blood clots in the arteries or veins of the legs, or in the lungs or other parts of the body (embolus)
- if you have angina (severe chest pain) or if you have had a myocardial infarction or stroke
- if you have porphyria (inherited metabolic disease due to an alteration in the metabolism of blood pigments)
- if you are hypersensitive to the active substances or to any of the excipients.
Precautions for use What you need to know before taking Vagifem
If you have any of the following conditions, please inform your doctor before starting "Vagifem':
- if 12 months have not yet passed since the last menstrual cycle
- if you have or have had severe liver disease in the past
- if you have irregular periods or recent vaginal bleeding
- if you have or have had "hyperplasia of the endometrium" (thickening of the lining of the womb)
- if you have any of the following rare hereditary problems: galactose intolerance, lactase deficiency, glucose / galactose malabsorption syndrome.
Pay particular attention when using "Vagifem":
Before starting HRT, your doctor will ask you about your personal and family medical history. Your doctor may have a breast and / or pelvic (lower abdomen) checkup and gynecological examination for you.
Once HRT has started, regular medical check-ups (at least annually) will still be done to accurately assess the risks and benefits of continuing therapy.
- Undergo mammography screening and vaginal cytology (PAP test) at regular intervals.
- Regularly check for any changes in the breasts such as small depressions in the skin, changes in the nipple, or any hardening that is visible or noticeable.
Some conditions can get worse during HRT. So if you have, have had in the past, or are at risk for any of the following conditions, your doctor may request more frequent checks:
- uterine fibroids or endometriosis (presence of uterine lining in abnormal locations) "
- formation of blood clots in the legs or lungs (see section "Blood clots")
- first degree family member who has or has ever had breast cancer or a tumor whose growth is sensitive to estrogen (such as cancer of the uterus or ovaries)
- hypertension (high blood pressure)
- liver disorders
- diabetes
- gallbladder stones
- migraine or severe headache
- systemic lupus erythematosus (autoimmune disease)
- epilepsy (disease leading to seizures)
- asthma
- otosclerosis (hereditary middle ear disease)
- hypertriglyceridaemia (increased blood triglycerides)
- heart or kidney failure.
If you notice a change in any of the above conditions and are taking Vagifem, tell your doctor.
Due to the topical administration of vagifem and the low concentrations of estradiol contained in it, the relapse or aggravation of the above conditions, as well as the appearance of the conditions mentioned above, is less likely than is observed with systemic estrogenic treatment.
You must stop treatment with "Vagifem" immediately and contact your doctor:
- if your skin turns yellow (jaundice)
- if you notice a significant increase in blood pressure
- if you notice a sudden severe headache (such as migraine)
- in case of pregnancy.
Effects on the cardiovascular system
Heart disease
HRT is not recommended for women who are suffering or have recently suffered from heart disease. If you have suffered from heart disease, tell your doctor about 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 spreading to your arm or neck and stop taking the drug until your doctor gives you permission to continue. This pain could be a symptom of heart disease.
Stroke
Recent research suggests a small increased risk of stroke related to HRT use. Other factors that may increase stroke risk include:
- age
- high blood pressure
- smoke
- excessive alcohol consumption
- irregular heartbeat.
Tell your doctor if you have any of the above factors or if you have had a stroke in the past to consider starting HRT..
Data in comparison
For women who are not users of HRT, about 3 cases of stroke per 1,000 women aged 50-59 years and about 11 per 1,000 women aged 60-69 years have been estimated over 5 years.
For women who use HRT, there are 4 strokes per 1,000 women aged 50-59 years and 15 per 1,000 women aged 60-69 years.
Inform your doctor immediately if you develop unexplained migraine-like headaches with or without visual disturbances, stopping taking the drug until your doctor authorizes you to continue.
A migraine-like headache could be an early symptom of a stroke.
Thrombus
HRT may increase the risk of blood 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 not dangerous most of the time, 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:
- if you are obese
- if you have had blood clots in the past
- if your first degree family member has had blood clots in the past
- if you have had one or more miscarriages
- if you have clotting problems that require treatment with anticoagulants (warfarin-like drugs)
- if you have to be immobilized for a long time due to major surgery, trauma or illness
- if you have a rare condition such as systemic lupus erythematosus (SLE).
Tell your doctor if you have any of the conditions listed above to consider starting HRT.
Data in comparison
For women who are not users of HRT, about 3 cases of VTE per 1,000 women aged 50-59 years and about 8 per 1,000 women aged 60-69 years have been estimated over 5 years.
For women who use HRT, cases of VTE become 7 per 1,000 women aged 50-59 years and 17 cases of VTE per 1,000 women aged 60-69 years.
Inform your doctor immediately if you experience painful edema of the lower limbs (swollen legs), sudden chest pain or difficulty in breathing, and stop taking the drug until your doctor authorizes you to continue. These problems could be symptoms of a thromboembolism.
Tell your doctor if you need to have surgery.
HRT will be stopped 4 to 6 weeks before surgery to reduce the risk of blood clots. Your doctor will advise you on resuming HRT.
Effects on cancer risk
Breast cancer
Women who have or have had breast cancer should not take HRT.
Taking HRT slightly increases the risk of breast cancer as well as a late onset of menopause.
The risk for a postmenopausal woman who has been taking estrogen-only HRT for 5 years is equivalent to that of a woman of the same age who is still menstruating at that time and who is not taking HRT. The risk for a woman taking combined estrogen / progestogen HRT is higher than for women taking estrogen alone (but the estrogen-progestagen combination has benefits for the endometrium, see section "Endometrial cancer").
For all HRTs, the additional risk of breast cancer becomes evident within a few years of initiating 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 1st degree relative (mother, sister or grandmother) who has had breast cancer
- if you are obese.
Data in comparison
Among women in their 50s who are not using HRT, around 32 breast cancers are diagnosed per 1,000 women in the period up to the age of 65. Among women who start estrogen-only HRT at age 50 and take it for 5 years, there will be 33-34 per 1,000 women diagnosed with breast cancer (1-2 additional cases).
If the intake is continued for 10 years, breast cancers diagnosed become 37 per 1,000 women (5 additional cases).
For women who start combined estrogen-progestagen HRT at age 50 and take it for 5 years, there will be 38 breast cancers diagnosed per 1,000 women (6 additional cases).
If the intake is continued for 10 years, the diagnosed breast cancers become 51 per 1,000 women (19 additional cases).
See your doctor as soon as possible if you experience breast changes such as small depressions in the skin, changes in the nipple, or any visible or perceptible hardening.
Endometrial cancer (cancer of the lining of the womb)
Taking estrogen-only HRT for a long time may increase your risk of endometrial cancer.
Taking a progestogen in addition to estrogen reduces the additional risk.
The dose of estradiol in Vagifem is low and the treatment is local. Modest systemic absorption may occur in some patients.
If the uterus is still present, your doctor will consider whether it is necessary to prescribe an estrogen-associated progestogen 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 the associated progestogen.
If the uterus has been partially removed due to endometriosis, any remaining endometrial remnants may be at risk. Your doctor will then discuss with you the appropriateness of taking estrogen-progestagen HRT.
Data in comparison
Among women who have uterus not treated with HRT, about 5 cases of endometrial cancer are diagnosed per 1,000 women aged 50-65.
Among women using estrogen-only HRT, the number increases 2 to 12-fold as a function of dose and duration of treatment.
Adding a progestogen to estrogen HRT substantially reduces the risk of endometrial cancer.
The appearance of intermenstrual bleeding or spotting (small intermenstrual discharge) especially during the first courses of treatment should not worry you.
See 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 discontinuation of 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 have indicated that taking estrogen-only HRT for more than 5 years increases the risk of ovarian cancer. It is not known whether other types of HRT may increase the risk in a similar way.
Dementia
HRT has no preventive effect on memory loss. A study in women starting combined estrogen-progestagen HRT after age 65 indicated a possible increased risk of dementia.
Other conditions
Women with hypertriglyceridaemia taking HRT may experience excessive increases in blood triglycerides which may lead to pancreatitis.
If you are taking thyroid replacement therapy (based on thyroxine) warn your doctor, who may require more frequent checks of thyroid function.
HRT can affect the results of some blood or urine tests. Tell your doctor that you are taking Vagifem if he asks you to have hormone tests.
Interactions Which drugs or foods may change the effect of Vagifem
Tell your doctor if you are taking or have recently taken any other medicines - even those not prescribed.
However, as Vagifem is administered locally and contains a low dose of estradiol, it is considered unlikely that interactions with other medicinal products will occur.
Warnings It is important to know that:
Pregnancy
"Vagifem" is not indicated in pregnancy.
If you are or suspect that you are pregnant, do not take this medicine. If you become pregnant, suspend this m
Feeding time
if you are breastfeeding, do not take this medicine.
Effects on ability to drive and use machines
Nobody.
Important information about some of the ingredients of "Vagifem"
Vagifem contains lactose. If your doctor has diagnosed you with "intolerance to some sugars, contact your doctor before taking this medicine."
Dosage and method of use How to use Vagifem: Dosage
Always use Vagifem exactly as your doctor has told you. If in doubt you should consult your doctor.
Dosage
Vagifem is administered intravaginally using the special applicator. Initial dose: one vaginal tablet a day for two weeks.
Maintenance dose: one vaginal tablet twice a week.
Treatment can be started on any day.
If a dose is missed, it should be taken as soon as you remember. Avoid taking a double dose.
For the initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose should be used for the shortest possible duration.
Vagifem can be used in both women with an intact uterus and hysterectomised women.
Minimal absorption may occur during treatment, especially in the first two weeks, but as plasma levels of estradiol after the first two weeks usually do not exceed those found in the postmenopausal period, the addition of a progestogen is not recommended.
Therapy should be continued only as long as the benefit obtained in relieving severe symptoms outweighs the risk.
Administration
- Take out a single blister pack and open it at the ends as shown. (Illustration)
- Carefully insert the applicator into the vagina until resistance is met. (Illustration)
- To release the tablet, press the button carefully until you hear a click. The tablet is thus immediately protected by the vaginal wall. It will not fall out if it is standing or walking. (illustration)
- Take out the applicator and throw it away.
Forgetting an application
Do not take double doses to replace what is forgotten. If you forget to take a vaginal tablet, take one as soon as you remember.
Missing one or more Vagifem tablets may increase the likelihood of breakthrough bleeding or spotting.
Overdose What to do if you have taken too much Vagifem
Symptoms of overdose may include: nausea, vomiting.
These symptoms disappear with discontinuation of treatment or reduction of the dosage.
In case of accidental intake of an excessive dose of the medicine, notify your doctor immediately or go to the nearest hospital.
IF YOU HAVE ANY DOUBTS ABOUT USING VAGIFEM, PLEASE CONTACT YOUR DOCTOR OR PHARMACIST.
Side Effects What are the side effects of Vagifem
Like all drugs, "Vagifem" can have side effects that generally disappear after the first months of treatment which can be divided as follows:
more than 640 patients have been treated with Vagifem in various clinical trials, including over 200 patients treated for 28-64 weeks. Adverse events definitely related to the administration of estrogens that occurred with a high incidence in the treatment group compared to untreated patients (placebo), are classified as "Common (> 1/100;
The spontaneous detection rate of Vagifem-related adverse events is approximately 1 case per 10,000 patient years. Adverse events for which no increased frequency was found in clinical trials, but which were spontaneously reported and which on unanimous opinion are to be considered possibly related to treatment with Vagifem are therefore classified as "Very rare (
Post-marketing experience is not subject to reporting, especially for mild and already recognized adverse reactions. The frequencies presented should therefore be interpreted in the light of the above.
The most reported adverse drug reactions are: bleeding and vaginal disorders. Adverse events related to estrogen therapy such as breast pain, peripheral edema and postmenopausal bleeding are most likely only present at the start of treatment with Vagifem.
The following adverse reactions have been reported in association with estrogen treatment:
- Myocardial infarction and heart disease
- Cholelithiasis
- Skin and subcutaneous tissue disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura, pruritus
- Vaginal candidiasis
- Risk of developing endometrial cancer (see section 4.4)
- endometrial hyperplasia or enlarged uterine fibroids *
- venous thromboembolism
- Insomnia
- Epilepsy
- Disorders of the libido
- Worsening of asthma
- Probable dementia (see section 4.4).
* In non-hysterectomised women
Usually, side effects aren't common and don't last long.
You will need to stop taking "Vagifem" and contact your doctor:
- if thrombus formation occurs (see section "Thrombus")
- if you suddenly have poor vision, severe headache or migraine (see section "Stroke")
- if you experience sudden chest pain that spreads to your arm or neck (see section "Heart disease")
- if your skin turns yellow (jaundice)
- in case of pregnancy.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Expiry and Retention
Keep Vagifem out of the reach and sight of children.
Do not use Vagifem after the expiry date which is stated on the label
The expiry date refers to the last day of the month.
The expiry date indicated refers to the product in intact packaging, correctly stored.
Do not store above 25 ° C. Do not refrigerate. Keep the container in the outer carton.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Vagifem contains
One film-coated vaginal tablet contains:
Active ingredients: estradiol 25 micrograms (as estradiol hemihydrate)
Excipients: hypromellose, lactose monohydrate, corn starch, magnesium stearat
Film coating: hypromellose and macrogol 6000.
What Vagifem looks like and contents of the pack
Vagifem comes in the form of film-coated vaginal tablets.
Each tablet is placed in a disposable applicator.
The applicators are packaged in blisters.
Each pack contains 15 applicators. The tablets are engraved with NOVO 279.
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
VAGIFEM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated vaginal tablet contains: Active ingredient. Estradiol: 25 mcg (as estradiol hemihydrate) of
For the full list of excipients see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated vaginal tablets.
White, biconvex film-coated tablets engraved with NOVO 279. Diameter: 6 mm.
Vagifem is in hydrophilic tablets, with matrix derived from cellulose which hydrates in contact with humidity, releasing 17β-estradiol.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Vagifem is indicated for the treatment of atrophic estrogen deficiency vaginitis.
Experience in treating women over the age of 65 is limited.
04.2 Posology and method of administration
Vagifem is administered intravaginally using the special applicator. Initial dose: one vaginal tablet a day for two weeks. Maintenance dose: one vaginal tablet twice a week.
Treatment can be started on any day. In case a dose is missed, it is best to take it as soon as you remember. It is best to avoid taking a double dose. For the initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose should be used for the shortest duration possible (see also section 4.4). Vagifem can be used in both women with an intact uterus and in hysterectomised women. During treatment. Minimal absorption may occur, especially in the first two weeks, but since plasma levels of estradiol after the first two weeks usually do not exceed those found in the postmenopausal period, the addition of a progestogen is not recommended. Therapy should be continued only as long as the benefit obtained in relieving severe symptoms outweighs the risk.
Administration
Open the blister from the button side.
Insert the applicator into the vagina until resistance is met (8-10 cm).
Release the tablet by pressing the button.
Remove the applicator and throw it away.
04.3 Contraindications
- Current, past or suspected breast cancer
- Current or suspected estrogen-dependent malignant tumors (e.g. endometrial cancer)
- Undiagnosed genital bleeding
- Untreated endometrial hyperplasia
- Previous or current idiopathic venous thromboembolism (deep vein thrombosis, pulmonary embolism)
- Known hypersensitivity to the active substance or to one of the excipients
- Porphyria
04.4 Special warnings and appropriate precautions for use
For the treatment of postmenopausal symptoms, hormone replacement therapy (HRT) should only be started if symptoms are such that they adversely affect quality of life. In all cases, a 'careful benefit and risk analysis should be done at least annually and HRT should only be continued if the benefits outweigh the risks.
Clinical examination / follow-up
Before initiating or reinstituting HRT, a complete personal and family medical history should be evaluated. The general and gynecological examination (including the physical examination of the pelvis and breasts) must be guided by the clinical history and by the contraindications and warnings for the use of the drug. During the treatment it is recommended to carry out periodic clinical checks whose frequency and nature must be adapted to each woman. Patients should be advised to report any changes in their breasts to their doctor (see "Breast cancer" below). Clinical investigations, including mammography, should be performed in line with currently accepted clinical protocols and the clinical needs of the individual case.
Conditions that require special control
In the event that any of the following conditions should arise, have manifested previously, and / or have worsened during a pregnancy or previous hormonal treatment, it would be advisable to carefully evaluate the woman. It should be noted that these conditions may recur or worsen during treatment with Vagifem, in particular:
- Leiomyoma (uterine fibroid) or endometriosis
- History or risk factors for thromboembolic disease (see below)
- Hypertension
- Hepatopathies (e.g. hepatic adenoma)
- Diabetes mellitus with or without vascular complications
- Cholelithiasis
- Migraine or (severe) headache
- Systemic lupus erythematosus
- History of endometrial hyperplasia (see below)
- Epilepsy
- Asthma
- Otosclerosis
Due to the topical administration of Vagifem and the low concentrations of estradiol contained in it, the relapse or aggravation of the above conditions is less likely than is observed with systemic estrogen treatment.
Reasons for immediate discontinuation of therapy
Therapy should be suspended if there are contraindications and in the following situations:
- Jaundice and deterioration of liver function - Significant increase in blood pressure
- Appearance of migraine-like headache
- Pregnancy
Endometrial hyperplasia
Women with an intact uterus with abnormal bleeding of uncertain etiology or women with an intact uterus previously treated with unbalanced estrogens should be carefully evaluated for possible hyperstimulation / malignant neoplasm of the endometrium before starting treatment with Vagifem. endometrial hyperplasia and carcinoma is increased following oral administration of estrogen alone for prolonged periods (see section 4.8). The addition of a progestogen for at least 12 days of the cycle in non-hysterectomised women significantly reduces this risk. The dose of estradiol in Vagifem is low and the treatment is local. Modest systemic absorption may occur in some patients. However, treatment with Vagifem is not associated with an increased risk of endometrial hyperplasia or uterine carcinoma. Since "no systemic effects are observed during topical estrogenic treatment with Vagifem, the choice of" any addition of a progestogen is postponed to the doctor's evaluation.
Generally, estrogen replacement therapy should not be prescribed for longer than one year without performing another clinical evaluation including gynecological examination. If breakthrough bleeding and spotting occur in the first months of treatment or if such episodes appear after some time from the start of therapy, or continue after discontinuation of therapy, the cause of these phenomena must be ascertained; also by means of biopsy of the "endometrium aimed at excluding malignant neoplasms of the endometrium. Unbalanced estrogen stimulation may lead to premalignant or malignant transformation of residual foci of endometriosis. The addition of progestogens to estrogen-only HRT is therefore recommended in women undergoing hysterectomy for endometriosis. especially in case of residual endometriosis.
Vagifem is a local low-dose estradiol preparation, therefore the recurrence of the following conditions is less likely than with systemic estrogenic treatment.
Breast cancer
A randomized placebo-controlled clinical trial, the Women's Health Initiative study (WHI) and epidemiological studies including the Million Women Study (MWS) have shown an increased risk of breast cancer in women who had been taking preparations based on breast cancer for many years. estrogen, or estrogen-progestogen combinations or tibolone for HRT (see section 4.8). For all drugs listed in HRT, an excess risk becomes evident within a few years of use and increases with duration of use but returns to baseline within a few (at most five) years after stopping treatment. In MWS, the relative risk of breast cancer with conjugated equine estrogens (CEE) or estradiol (E2) was higher when a progestogen was added both in sequential regimen and continuous regimen regardless of the type of progestin. There was no evidence of a different risk between the different modes of administration. In the WHI study, continuous combined administration of conjugated equine estrogen and medroxyprogesterone acetate (CEE + MPA) was associated with breast cancers that were slightly larger. and had more frequent metastases in local lymph nodes than placebo. HRT, especially estrogen-progestogen combination preparations, increases the density of mammography images which may adversely affect the radiological detection of breast cancer.
Venous thromboembolism
HRT is associated with an increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. A randomized controlled trial and some epidemiological studies have shown a 2 to 3-fold increased risk in women who are taking HRT compared to women who are not users of HRT. In the latter, it is estimated that the number of cases of venous thromboembolism that will occur over a period of 5 years is approximately 3 cases per 1000 women aged between 50 and 59 years, and 8 per 1000 women aged between 60 and 69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of venous thromboembolism over a 5-year period is 2-6 cases (best estimate = 4) per 1000 women of age. 50-59 years and 515 cases (best estimate = 9) per 1000 women aged 60-69. These events are more likely to occur in the first year of HRT than in subsequent years. Generally recognized risk factors for venous thromboembolism they include: a family or personal history, severe obesity (BMI> 30 kg / m2), systemic lupus erythematosus. There is no consensus on the possible role of varicose veins in venous thromboembolism. Patients with a history of venous thromboembolism or with known thrombophilic states have an increased risk of venous thromboembolism. HRT may increase this risk. A "personal or family history of thromboembolic episodes, or recurrent spontaneous abortions, should be well evaluated in order to exclude a predisposition to thrombosis. Until" a complete evaluation of thrombophilic factors has been performed or anticoagulant therapy initiated, recourse HRT in such women should be regarded as contraindicated. Women already being treated with anticoagulants require careful assessment of the benefit / risk ratio of HRT.
The risk of venous thromboembolism may "be temporarily increased in the event of prolonged immobilization, trauma or major surgery. As in all patients, in the postoperative period particular attention should be paid to prophylaxis measures aimed at preventing episodes of venous thromboembolism resulting from Surgery. When prolonged immobilization is anticipated following elective surgery, particularly abdominal surgery or orthopedic surgery of the lower limbs, temporary discontinuation of HRT should be considered if possible 4-6 weeks prior to surgery. HRT should not be resumed until after complete mobilization of the woman.
If venous thromboembolism develops after initiation of therapy, the drug should be discontinued. Women should be advised to contact their physician immediately if symptoms referable to venous thromboembolism occur (eg swollen and painful lower limb, sudden chest pain , dyspnoea),
Coronary heart disease (CAD)
Randomized controlled trials show no cardiovascular benefit in continuous combined treatment with conjugated estrogens and medroxyprogeserone acetate (MPA). Two large clinical trials (WHI and HERS or Heart and Estrogen / progestin Replacement Study) show a possible increased risk of cardiovascular morbidity in the first year of treatment and no overall benefit. For other types of HRT there are only limited data available. from randomized controlled trials that have examined the effects on cardiovascular morbidity or mortality. Therefore, it is questionable whether these conclusions can also be extended to HRT with other products.
A large randomized clinical trial (WHI-trial) showed, as a secondary effect, an increased risk of ischemic stroke in healthy women during continuous combination therapy with conjugated estrogens and MPA. In women not treated with HRT, the number of stroke cases that can occur over a 5-year period is estimated to be around 3 per 1000 women aged 50-59 and 11 per 1000 women aged 60-69. It is estimated that for women using conjugated estrogen and MPA for 5 years, the number of additional cases is between 0 and 3 (best estimate = 1) per 1000 women aged 50-59 and between 1 and 9 (best estimate = 4) per 1000 women aged 60-69. It is not known whether this increased risk also extends to HRT with other products.
Long-lasting (at least 5-10 years) estrogen-only HRT in hysterectomised women has been shown in some epidemiological studies to be associated with an increased risk of ovarian cancer. It is uncertain whether long-term HRT with combination products involves a different risk from that present with estrogen alone.
Dementia
There is no conclusive evidence of improved cognitive function. From the WHI study there is any evidence of an increased risk of probable dementia in women starting continuous combined conjugated estrogen (CEE) + MPA treatment after age 65. . It is not known whether these findings apply to younger postmenopausal women or to other HRT products. Other conditions Estrogens can cause water retention, and therefore it is advisable to carefully monitor women with heart disease or kidney disease. Women with end-stage renal failure should be observed with particular attention since "it is reasonable to expect an increase in the circulating concentrations of active substances. contained in Vagifem.
Other conditions
Women with pre-existing hypertriglyceridaemia should be followed closely throughout the period of estrogen therapy or HRT. Since ", in this condition, cases of sharp increase in plasma concentrations of triglycerides and consequent pancreatitis following estrogen therapy have been reported.
Estrogen increases the levels of TBG, the thyroid-binding globulin, resulting in an increase in circulating levels of total thyroid hormones, measured as protein-bound iodine (PBI), levels of T4 (by column chromatography or radioimmunoassay) or T3 levels (by radioimmunoassay). Resin uptake of T3 is "reduced: this reflects the" increase in TBG. Free fractions of T4 and T3 remain unaffected. Other serum binding proteins such as corticosteroid-binding globulin (CBG) may also be increased in serum. sex hormone binding globulin (SHBG), inducing an increase in circulating levels of corticosteroids and sex hormones, respectively. Concentrations of free or biologically active hormones are unaltered. Other plasma proteins may be increased (angiotensinogen substrate / renin, alpha- Iantitrypsin, ceruloplasmin).
Information about some of the ingredients of Vagifem
Vagifem contains lactose: patients with rare hereditary problems of galactose intolerance, the lactase deficiency, or glucose / galactose malabsorption should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
Since "the low doses of estradiol contained in Vagifem are administered locally, no clinically relevant interactions are expected.
04.6 Pregnancy and breastfeeding
Pregnancy
Vagifem is not indicated during pregnancy. If pregnancy occurs during treatment with Vagifem, treatment should be discontinued immediately. The results of most epidemiological studies on involuntary fetal exposure to estrogen indicate that there is no teratogenic or foetotoxic effect.
Feeding time
Vagifem is not indicated during lactation.
04.7 Effects on ability to drive and use machines
No known effects.
04.8 Undesirable effects
More than 640 patients have been treated with Vagifem in various clinical trials, including over 200 patients treated for 28-64 weeks.Adverse events definitely related to the administration of estrogens that occurred with a high incidence in the treatment group compared to untreated patients (placebo), are classified as "Common (> 1/100;
The spontaneous detection rate of Vagifem-related adverse events is approximately 1 case per 10,000 patient / year. Adverse events for which no increased frequency was found in clinical trials, but which were spontaneously reported and which on unanimous opinion are to be considered possibly related to treatment with Vagifem are therefore classified as "Very rare (
Post-marketing experience is not "subject to reporting, especially for mild and already" recognized adverse reactions. The frequencies presented should therefore be interpreted in the light of the above.
The most reported adverse drug reactions are: bleeding and vaginal disorders. Adverse events related to estrogen therapy such as breast pain, peripheral edema and postmenopausal bleeding are most likely only present at the start of treatment with Vagifem.
The following adverse reactions have been reported in association with estrogen treatment:
- Myocardial infarction and heart disease
- Cholelithiasis
- Skin and subcutaneous tissue disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura, pruritus
- Vaginal candidiasis
- Risk of developing endometrial cancer (see section 4.4),
- endometrial hyperplasia or enlargement of uterine fibroids *
- venous thromboembolism
- Insomnia
- Epilepsy
- Disorders of the libido
- Worsening of asthma
- Probable dementia (see section 4.4)
* In non-hysterectomised women The following adverse reactions have been reported with systemic estrogen or estrogen-progestagen HRT:
* Breast cancer
According to evidence from a large number of epidemiological studies and a randomized placebo-controlled study, the Women's Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use. in patients under treatment and in those who have recently used it.
For estrogen-only HRT, it is estimated that the relative risk (RR) evidenced by a re-analysis of the original data from 51 epidemiological studies (in which more than 80% of hormone replacement therapies were with estrogen alone) and from from the Million Women Study (MWS) epidemiological study, it is similar to 1.35 (95% CI 1.21-1.49) and 1.30 (95% CI 1.21-1.40) respectively.
For combined HRT with estrogen plus progestogen, several epidemiological studies have reported an overall higher risk of breast cancer than estrogen alone.
The MWS study reported that the use of various types of combined estrogen-progestagen HRT was associated with a higher risk of breast cancer compared to women who never received therapy (RR = 2.00, 95% CI: 1.88 - 2.12) compared to the use of estrogen only (RR = 1.30, 95% CI: 1.21 - 1.40) or the use of tibolone (RR = 1.45; 95% CI 1.25 - 1.68).
The WHI study reported an estimated risk of 1.24 (95% CI 1.01 - 1.54) after 5.6 years of combined estrogen-progestogen HRT (EEC + MPA) treatment in all users compared to placebo.
The absolute risks calculated by the MWS and WHI studies are shown below:
The MWS has estimated, based on the known mean incidence of breast cancer in developed countries, that:
• For women not using HRT, around 32 in 1000 women are expected to be diagnosed with breast cancer between the ages of 50 and 64. For 1000 women who use or have recently used HRT, the number of additional cases during the corresponding period will be:
For users of estrogen-only replacement therapy
Between 0 and 3 (best estimate = 1.5) for 5 year use
Between 3 and 7 (best estimate = 5) for 10 year use.
For users of combined estrogen plus progestogen HRT
between 5 and 7 (best estimate = 6) for a 5 year use
between 18 and 20 (best estimate = 19) for 10-year use
The WHI study estimated that after 5.6 years of follow-up in women aged 50 to 79 years, 8 more invasive breast cancer cases per 10,000 women / year would be due to combined estrogen-progestogen HRT (CEE + MPA ). According to the calculations extrapolated from the clinical study data, it is estimated that:
* For 1000 women in the placebo group,
or about 16 cases of invasive breast cancer would be diagnosed within 5 years
* For 1000 women who used combined estrogen + progestogen HRT (CEE + MPA), the number of additional cases would be
Between 0 and 9 (best estimate = 4) for 5 years use
The number of additional cases of breast cancer in women using HRT is broadly similar for all women starting HRT regardless of the age of initiation of therapy (between 45 and 65) (see section 4.4).
Endometrial cancer
In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unbalanced estrogen. According to data from epidemiological studies, the best estimate of the risk is that for women who do not use HRT, about 5 cases of endometrial cancer are expected to be diagnosed in every 1,000 women between the ages of 50 and 65. Depending on the duration of treatment and the dose of estrogen, the reported increased risk of endometrial cancer in women who use unbalanced estrogen is 2 to 12 times greater than in those who do not.
By adding a progestogen to estrogen-only therapy, this high risk is greatly reduced.
** Venous thromboembolism such as deep vein thrombosis in the legs or pelvic and pulmonary embolism, is much more common among HRT users than non-users. For more information see section 4.3 Contraindications and 4.4 Special warnings and precautions for use.
04.9 Overdose
No cases of overdose have been reported.
Vagifem is "intended for local intravaginal treatment. The dose of estradiol is" so low that a considerable number of tablets would have to be administered to approach the dose usually used for systemic use. Treatment must be symptomatic.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Natural and semisynthetic non-associated estrogens ATC G03CA03
Natural and semi-synthetic estrogens, simple (for vaginal use). The active formulation, the synthetic 17β-estradiol, is chemically and biologically identical to the endogenous human estradiol. Endogenous 17β-estradiol induces and maintains secondary and primary female sexual characteristics. The biological effect of 17β-estradiol is carried out through a series of specific receptors. The steroid receptor complex binds to cellular DNA and induces the synthesis of specific proteins. The maturation of the vaginal epithelium depends on estrogens. These increase the number of superficial and intermediate cells compared to basal cells. Estrogen maintains vaginal pH below 4.5 which favors the growth of normal bacterial flora, with Lactobacillus Döderlein predominating.
05.2 "Pharmacokinetic properties
An estrogenic drug is well absorbed through the skin, mucous membranes and the gastrointestinal tract. Vaginal administration of estrogen bypasses the first metabolic stage. A randomized, double-blind, double-period crossover single-center study was performed to evaluate the pharmacokinetics of Vagifem. Following single-dose administration of Vagifem, maximum plasma concentrations were approximately 175 pmol / L (48 pg / ml) After 14 days of treatment, only a marginal absorption of 17β-estradiol can be found, with average levels in the postmenopausal range. Another study in younger patients, mean age 52 years, showed that vaginal application of Vagifem for 12 weeks induced a mean estradiol C of 50 pg / ml and no significant accumulation of estradiol was observed in terms of AUC0. -24 (See Table 1). The mean concentrations of 17β-estradiol at each point on the curve were within the normal postmenopausal range. Table 1
Mean pharmacokinetic parameters (β standard deviation) for estradiol
The levels of estrone observed during the 12 weeks of treatment with Vagifem showed no accumulation and the values found were within the normal postmenopausal range. The metabolites of estrogens are mainly excreted in the urine as glucuronides and sulfates.
05.3 Preclinical safety data
Since "17β-estradiol is" a well known substance, described in the pharmacotoxicological literature, no further studies have been performed.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Tablet: Hypromellose Lactose monohydrate Maize starch Magnesium stearate
Film coating: Hypromellose Macrogol 6000
06.2 Incompatibility
Not relevant
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Do not store above 25 ° C. Do not refrigerate. Keep the container in the outer carton.
06.5 Nature of the immediate packaging and contents of the package
Each tablet is placed in an easy-to-use disposable polyethylene / polypropylene applicator. The applicators are packed in PVC / aluminum blisters. Each package contains 3 blisters each consisting of 5 applicators containing the tablets.
06.6 Instructions for use and handling
No special instructions
07.0 MARKETING AUTHORIZATION HOLDER
Novo Nordisk A / S, 2880 Bagsvaerd, Denmark
08.0 MARKETING AUTHORIZATION NUMBER
AIC n.028894018
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
April 22, 1995
