Active ingredients: Estradiol, Nomegestrol (Nomegestrol acetate)
NEAMIS tablets
Indications Why is Naemis used? What is it for?
NAEMIS® is a hormone replacement therapy (HRT). It contains two active ingredients: an estrogen (estradiol) and a progestin (Nomegestrol acetate).
These substances act like the natural hormones present in the body.
NAEMIS® is used for:
Relief from symptoms that appear after menopause
During menopause, the amount of estrogen produced by a woman's body decreases. In some women, this can cause symptoms such as hot flashes of the face, neck and chest. NAEMIS® relieves these postmenopausal symptoms. You will be prescribed NAEMIS® only if symptoms severely hamper your daily life.
Experience in the treatment of women over the age of 65 is limited.
Contraindications When Naemis should not be used
Do not take NAEMIS® if any of the following conditions apply to you. If you are unsure of any of the points below, consult your doctor before taking NAEMIS®.
- If you have or have ever had breast cancer, or if you are suspected of having it.
- If you have estrogen sensitive cancer, such as cancer of the lining of the womb (endometrium), or if you suspect you have it.
- If you have unexplained vaginal discharge.
- If you have excessive thickening of the lining of the womb (endometrial hyperplasia) that is not treated.
- If you have or have had a blood clot in a vein (thrombosis), such as in the legs (deep vein thrombosis) or in the lungs (pulmonary embolism).
- If you have a blood clotting disorder (such as protein C, protein S or antithrombin deficiency).
- If you have or have recently had a disease caused by blood clots in the arteries, such as heart attack, stroke or angina.
- If you have or have had liver disease and liver function tests have not returned to normal
- If you have a rare blood problem called 'porphyria' which is passed on (by inheritance).
- If you are allergic (hypersensitive) to estradiol hemihydrate and / or nomegestrol acetate or any of the other ingredients of NAEMIS® (listed in section 6 Contents of the pack and other information).
If any of the above conditions appear for the first time while taking NAEMIS®, stop taking it immediately and consult your doctor immediately.
Precautions for use What you need to know before taking Naemis
Medical history and regular checkups
The use of HRT carries risks that need to be considered when deciding whether to start taking it or continue with it.
There is limited experience in treating women with premature menopause (due to ovarian or surgical failure). If you have premature menopause the risks of using HRT may be different. Contact your doctor.
Before starting (or restarting) HRT, your doctor will ask you a few questions about your personal and family medical history. Your doctor may decide to have you undergo a medical examination. This may include a breast checkup and / or an internal visit if needed.
Once you have started taking NAEMIS®, go to your doctor for regular check-ups (at least once a year). During these checkups, your doctor will need to discuss the benefits and risks of continuing NAEMIS® therapy.
Get regular breast checks as recommended by your doctor.
Before starting treatment, tell your doctor if you have ever had any of the following problems as they may come back or get worse during treatment with NAEMIS®. In this case, you need to see your doctor more often for check-ups:
- Fibroids inside the uterus
- Growth of the lining of the womb outside the womb (endometriosis) or a history of abnormal growth of the lining of the womb (endometrial hyperplasia)
- Increased risk of developing blood clots (see "Blood clots in a vein (thrombosis)")
- Increased risk of developing estrogen sensitive cancer (such as having a mother, sister or grandmother who has had breast cancer)
- High blood pressure
- Liver disorder, such as a benign liver tumor
- Diabetes
- Gallstones
- Migraine or severe headache
- A disease of the immune system that affects many organs of the body (systemic lupus erythematosus, SLE)
- Epilepsy
- Asthma
- A disease affecting the eardrum and hearing (otosclerosis)
- A very high level of fat in the blood (triglycerides)
- Water retention caused by kidney or heart problems
Stop taking NAEMIS® and see your doctor immediately
If you notice any of the following while taking HRT:
- Any conditions mentioned in the "Do not take NAEMIS®" section
- Yellowing of the skin and whites of the eyes (jaundice). These could be signs of liver disease
- Significant increase in blood pressure (symptoms can be headache, tiredness, dizziness)
- Migraine-like headaches appearing for the first time
- If you become pregnant
- If you notice signs of a blood clot such as:
- Painful swelling and redness of the legs
- Sudden chest pain
- Respiratory difficulties.
For more information, see "Blood clots in a vein (thrombosis)"
Also, you should tell your doctor if:
- you have to undergo surgery
- must remain immobilized for an extended period of time
- he contracted another disease
Note: NAEMIS® is not a contraceptive. If it has been less than 12 months since your last period or you are under the age of 50, you may still need to use an additional method of contraception to prevent pregnancy. Consult with your doctor.
HRT and cancer
Excessive thickening of the lining of the womb (endometrial hyperplasia) and cancer of the lining of the womb (endometrial cancer).
Taking estrogen-only HRT will increase your risk of 'excessive thickening of the lining of the womb (endometrial hyperplasia) and cancer of the lining of the womb (endometrial cancer).
The NAEMIS® progestin protects you from this extra risk.
In women who still have a uterus and are not taking HRT, on average, 5 in 1,000 cases of endometrial cancer are diagnosed between the ages of 50 and 65.
For women between the ages of 50 and 65 who still have a uterus and who are taking estrogen-only HRT, between 10 and 60 women in 1,000 will be diagnosed with endometrial cancer. to 55 more cases), depending on the dose and period of intake.
Unexpected bleeding
You will still have your period once a month (so-called withdrawal bleeding) while taking NAEMIS®. However, if you have unexpected bleeding or drops of blood (spotting) in addition to your monthly period, which:
- They last for more than the first 6 months.
- They start after taking NAEMIS® for more than 6 months.
- They last after you stop taking NAEMIS®.
Consult your doctor as soon as possible.
Breast cancer
Evidence suggests that taking combined estrogen-progestagen HRT and possibly also estrogen-only HRT increases the risk of breast cancer. The additional risk depends on the length of the HRT period. The additional risk becomes apparent by the time you take it. a few years. However, it returns to normal within a few years (at most 5) after stopping treatment.
Women between the ages of 50 and 79 who are not taking HRT, on average 9-17 in 1,000 will be diagnosed with breast cancer over a 5-year period.
For women aged 50 to 79 who have been taking estrogen-progestogen HRT for more than 5 years, there will be 13 to 23 cases in 1,000 users (e.g. an increase from 4 to 6 cases).
Check your breasts regularly. Consult your doctor if you notice any changes such as:
- Skin retraction
- Changes in the nipple
- Nodules you can see or hear
Ovarian cancer
Ovarian cancer is rare. A slightly increased risk of ovarian cancer has been reported in women taking HRT for at least 5 to 10 years. Women between the ages of 50 and 69 who are not taking HRT, on average about 2 in 1,000 women will be diagnosed with ovarian cancer over a 5-year period.For women who have taken HRT for 5 years, there will be between 2 to 3 cases per 1,000 users (Ex: 1 extra case).
EFFECT OF TOS ON HEART AND CIRCULATION
Blood clots in a vein (thrombosis)
Tell your doctor right away if you experience painful swelling in one of your legs, sudden chest pain or shortness of breath while taking NAEMIS®. This could be a sign of deep vein thrombosis or pulmonary embolism, in which case you should stop taking it immediately. taking NAEMIS®.
The risk of blood clots in the veins is about 1.3 to 3 times higher in women taking HRT than in those not taking it, especially during the first year of taking it.
Blood clots can be serious, and if one goes back to the lungs it can cause chest pain, breathlessness, fainting or even death.
You are at greater risk of developing a blood clot in your veins as you get older and if any of the following apply to you. Tell your doctor if you are in any of the following situations:
- Cannot walk for a long time due to major surgery, injury or illness (see also section 3, If you need to have surgery)
- If you are severely overweight
- If you have a blood clotting problem that requires long-term treatment with a medicine used to prevent blood clots
- If any of your close relatives have had a blood clot in the legs, lungs or another organ
- If you have systemic lupus erythematosus (SLE)
- If you have cancer
If you have any of these conditions, please tell your doctor. If you are using a blood thinner, the risks and benefits of using HRT should be carefully weighed.
For signs of a blood clot, see "Stop taking NAEMIS® and see your doctor immediately".
Looking at women in their 50s who are not taking HRT, on average, over a 5-year period, 4 to 7 in 1,000 could develop a blood clot in a vein.
For women in their 50s who have been taking estrogen-progestogen HRT for more than 5 years, there may be 9 to 12 cases in 1000 women (e.g. 5 extra cases).
Heart disease (heart attack)
Stop taking NAEMIS® and contact your doctor immediately if you develop chest pain that extends to your arm or neck. The pain may be a sign of heart disease.
There is no evidence that HRT helps prevent a heart attack.
Women over the age of 60 who use estrogen-progestagen HRT are slightly more at risk of developing heart disease than those who are not taking HRT. Since the risk of coronary heart disease (CAD) is highly age-dependent, the number of additional cases of coronary heart disease due to estrogen-progestogen use is very low in healthy women close to menopause, but increases with advancing age. .
Stroke
Stop taking NAEMIS® and contact your doctor immediately if you develop: Unexplained migraine-like headaches, with or without visual disturbances. These headaches can be an early sign of a stroke.
The risk of having a stroke is about 1.5 times higher in women who take HRT than in those who do not. The number of additional cases of stroke due to HRT use increases with increasing age.
Looking at women in their 50s who are not taking HRT, on average, 8 in 1,000 could have a stroke over a 5-year period. For women in their 50s who are taking HRT, there will be 11 cases in 1,000 women over 5 years (eg: 3 more cases).
Other conditions
TOS does not prevent memory loss. There is some evidence of an increased risk of memory loss in women who start using HRT after the age of 65.
Consult with your doctor.
Interactions Which drugs or foods may change the effect of Naemis
Some medicines can interfere with the effect of NAEMIS®. This can cause irregular bleeding. This condition affects the following medicines:
- medicines for epilepsy (such as phenobarbital, phenytoin and carbamazepine)
- medicines for tuberculosis (such as rifampicin, rifabutin)
- medicines for HIV infections (such as nevirapine, efavirenz, ritonavir and nelfinavir)
- phytopreparations containing St. John's wort (Hypericum perforatum).
Tell your doctor or pharmacist if you are taking, have recently taken and must take any other medicines.
Warnings It is important to know that:
Laboratory analysis
If you need to have a "laboratory test", tell your doctor or laboratory staff that you are taking NAEMIS®, as this medicine can alter the results of some tests.
Pregnancy and breastfeeding
NAEMIS® is intended for use by postmenopausal women only. Do not take this medicine if you are pregnant or breastfeeding. If you become pregnant, stop taking NAEMIS® and contact your doctor.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
No specific undesirable effects are expected.
NAEMIS® contains lactose
Due to the presence of lactose, you should not take this medicine if you have rare hereditary problems such as galactose intolerance.
NAEMIS® contains cochineal red (E124)
Due to the presence of cochineal red (e124), there is a risk of an allergic reaction.
Dose, Method and Time of Administration How to use Naemis: Posology
Always take NAEMIS® exactly as your doctor has told you. If you have any questions, consult your doctor or pharmacist.
Dosage regimen
Take 1 pink tablet a day for ten days, then 1 white tablet a day for 14 consecutive days.
Swallow the tablet with water with or between meals, preferably at the same time of day.
It is a 24-day treatment with a 4-day drug-free interval.
In clinical studies, this method of administration resulted in regular menstrual cycles, averaging every 28 days. Menstrual cycles appear on average 4 days after taking the last tablet and last about 5 days. The next sequence will start again after a 4 day break, even if the menstrual cycle is not finished yet.
Take the tablets in the following order: 10 pink tablets and then 14 white tablets.
First day
You start the pack with the pink tablet marked 1.
On the side of the pack there is a weekly calendar which will help you keep track of the day you took your first tablet.
Following days
Follow the order of taking the tablets using the arrows.
Each treatment sequence is followed by the onset of the menstrual cycle, which occurs 4 days after taking the last tablet and lasts approximately 5 days.
Subsequent packs
Start the next pack after a 4-day break, regardless of your menstrual cycle.
For example, if you started your first pack on a Monday, you should always start the next packs on a Monday, even if your period hasn't finished.
If you are not taking HRT or have switched to this medicine after a continuous combined HRT product, treatment can be started on any day that is convenient for you.
If you are coming from sequential HRT, treatment should start the day after completing the previous regimen.
Your doctor will tend to prescribe the lowest dose to treat your symptoms for as short a time as possible. Consult with your doctor if you think this dose is too strong or insufficient.
Method of administration
Oral way
Duration of treatment
The doctor will determine the duration of the treatment.
Contact your doctor if you wish to stop treatment.
If you forget to take NAEMIS®
If you realize you have forgotten to take a tablet within 12 hours of the usual time, take the forgotten tablet immediately.
Otherwise, throw away the forgotten tablet and continue treatment as normal by taking one tablet the next morning. If you have any further questions, please ask your doctor.
Do not take a double dose to make up for the forgotten tablet.
If you stop taking NAEMIS®
Peri-menopausal signs linked to a lack of estrogen may reappear.
If you have any further questions, ask your doctor or pharmacist.
If you need to have surgery
If you are due to have surgery, please inform your surgeon that you are taking NAEMIS®. You may need to stop taking NAEMIS® approximately 4 to 6 weeks before your surgery to decrease the risk of a blood clot (see section 2, Blood clots in a vein).
Ask your doctor when you can start taking NAEMIS® again.
Overdose What to do if you have taken too much Naemis
Overdose is unlikely, but it can cause the following:
- Breast pain
- Abdominal bloating, flatulence, nausea and vomiting
- Irritability, anxiety
- Vaginal bleeding.
If the signs persist, consult with your doctor.
There is no antidote but symptoms can be treated.
Side Effects What are the side effects of Naemis
Like all medicines, this medicine can cause side effects, although not everybody gets them. Most of the effects seen with NAEMIS® are mild to moderate and do not require discontinuation of treatment.
If the following symptoms persist, consult with your doctor, who may adjust your treatment: flushing, headache, uncomfortable vaginal dryness, nausea, vomiting, abdominal pain, chest tightness, eye irritation from contact lenses, irritability , heavy legs and weight gain.
In case of severe or irregular gynecological bleeding, consult with your doctor.
The following diseases are reported more frequently in women taking HRT compared to those not using it:
- breast cancer
- abnormal growth or cancer of the lining of the womb (endometrial hyperplasia or cancer)
- ovarian cancer
- blood clots in the leg veins or lungs (venous thromboembolism)
- heart disease
- stroke
- probable memory loss if HRT is started after the age of 65.
For more information on these side effects, see section 2.
The following side effects can be very common (may affect more than 1 in 10 people):
- Breast pain (mastodynia).
- Mild but persistent uterine / vaginal bleeding (spotting)
- intercurrent bleeding
The following side effects may be common (may affect up to 1 in 10 people):
- Irregular and abnormal uterine bleeding (menorrhagia)
- Menstrual disturbances
- Vaginal discharge (leukorrhea)
- Aggravation of uterine fibroids
- Abdominal pain, swelling, pelvic pain, dysmenorrhea
- Headache
- Muscle cramps, pain in the limbs
- Nervousness, depression
- Weight gain
The following side effects may be uncommon (may affect up to 1 in 100 people):
- Benign breast cancer
- Uterine polyp
- Vaginal candidiasis
- Breast augmentation
- Endometriosis
- He retched
- Constipation
- Diarrhea
- Migraine
- Dizziness
- Blood clot (thrombophlebitis, pulmonary embolism, superficial or deep vein thrombosis)
- Hypertension
- Swelling in the ankle, feet or fingers
- Peripheral edema
- Feeling of weakness (asthenia)
- Increased appetite
- Rash
- Tingling (itching)
- Hair loss (alopecia)
- Abnormal liver values
The following side effects have been reported with other HRTs:
- Diseases of the gallbladder
- Various skin disorders:
- A change in the color of the skin, especially of the face or neck, known as "pregnancy spots" (chloasma).
- Painful reddish skin nodules (erythema nodosum).
- Rash with target redness or lesions (erythema multiforme).
- Appearance of purple spots on the skin (vascular purpura)
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 through the Italian Medicines Agency Website: www.agenziafarmaco.it/it/responsabili By reporting side effects you can help provide more information on the 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 carton after EXP. The expiry date refers to the last day of that month.
Store below 25 ° C.
Do not take this medicine if you notice any visible signs of deterioration.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment. This will help protect the environment.
Other information
What NAEMIS® contains
The active ingredients are:
- Pink tablet: 1.5 mg of estradiol (in the form of 1.55 mg of estradiol hemihydrate).
- White tablet: 1.5 mg of estradiol (in the form of 1.55 mg of estradiol hemihydrate) and 3.75 mg of nomegestrol acetate.
The other ingredients are:
- Pink tablet: povidone (K25 or K30), lactose monohydrate, microcrystalline cellulose, glycerol distearate, colloidal anhydrous silica, crospovidone, cochineal red A (E124), aluminum lake.
- White tablet: povidone (K25 or K30), lactose monohydrate, microcrystalline cellulose, glycerol distearate, anhydrous colloidal silica, crospovidone.
Description of the appearance of NAEMIS® and contents of the pack
Each blister (PVC / PE / ACLAR / Aluminum) contains 10 pink and 14 white tablets.
Not all pack sizes may be marketed.
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
NAEMIS TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Pink tablet :
Each pink tablet contains 1.5 mg of estradiol (equivalent to 1.55 mg of estradiol hemihydrate).
Excipients with known effect: lactose monohydrate (135.745 mg) and cochineal red A (E124), aluminum lake.
White tablet :
Each white tablet contains 1.5 mg of estradiol (equivalent to 1.55 mg of estradiol hemihydrate) and 3.75 mg of nomegestrol acetate.
Excipient with known effect: lactose monohydrate (130.175 mg).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Tablets.
Round pink tablets and round white tablets.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Hormone replacement therapy (HRT) for the treatment of estrogen deficiency symptoms in women who have not had a period for at least 6 months.
04.2 Posology and method of administration
Oral administration.
NAEMIS is a "cyclical association of estrogen and progestin.
The therapeutic scheme is as follows:
One tablet per day for 24 consecutive days in the following order:
• from day 1 to day 10, one pink tablet (estradiol);
• from day 11 to day 24, a white tablet (estradiol combined with nomegestrol acetate).
After a 4-day withdrawal period, resume taking the drug according to the previous schedule, even if the withdrawal bleeding is still in progress.
In women who have never received HRT or who have switched from continuous combined HRT, NAEMIS can be started on any day of the cycle.
However, if the patient is routinely using sequential HRT, the current treatment should be completed before starting NAEMIS.
If the patient forgets to take a tablet, treatment should be continued as prescribed (two tablets should not be taken to counterbalance the single missed dose). Forgetting to take a tablet can increase the likelihood of intercurrent bleeding or spotting.
The lowest effective dose for the shortest duration should be used to initiate and continue treatment of postmenopausal symptoms (see also section 4.4).
04.3 Contraindications
• Known, past or suspected breast cancer
• Known or suspected estrogen-dependent malignant neoplasms (eg endometrial cancer)
• Undiagnosed genital bleeding
• Untreated endometrial hyperplasia
• Previous or current venous thromboembolism (deep vein thrombosis, pulmonary embolism)
• Known thrombophilic disorders (eg protein C, protein S or antithrombin deficiency, see section 4.4)
• Current or recent arterial thromboembolic disease (eg angina, myocardial infarction)
• Severe liver disease or liver disease in history, until liver function has returned to normal
• Known hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
• Porphyria.
04.4 Special warnings and appropriate precautions for use
For the treatment of postmenopausal symptoms, HRT should only be initiated in the presence of symptoms that adversely affect quality of life. In all cases, a "careful evaluation of the risks and benefits should be done at least annually and HRT should only be continued as long as the benefits outweigh the risks.
There is limited evidence regarding the risks associated with HRT in the treatment of premature menopause. However, given the low level of absolute risk in younger women, the balance of benefits and risks for these women may be more favorable than that in older women. elderly.
Clinical examination and medical checks :
Before initiating or resuming hormone replacement therapy, a complete personal and family medical history of the patient should be taken. The physical examination (including that of the pelvis and breast) should be conducted taking into account the clinical history, contraindications and precautions for use. During the treatment, it is recommended to carry out periodic checks whose nature and frequency must be established according to each patient.
Women should be advised what changes in their breasts should be reported to their doctor or healthcare professional (see "Breast Cancer" below).
Exams, including diagnostic imaging such as eg. mammography, should be conducted in accordance with current accepted screening practices, modified according to individual clinical needs.
Conditions that require close medical supervision
If any of the following conditions are present, have occurred in the past and / or have worsened during pregnancy or previous hormone treatment, the patient should be closely monitored. It should be taken into account that the conditions listed below may recur or worsen during therapy with NAEMIS. Particularly:
• Leiomyoma (uterine fibroids) or endometriosis;
• Risk factors for thromboembolic disorders (see below);
• Risk factors for estrogen-dependent cancers (eg first degree relatives with breast cancer);
• Hypertension;
• Liver changes (eg hepatic adenoma);
• Diabetes mellitus with or without vascular involvement;
• Cholelithiasis;
• Migraine or (severe) headache;
• Systemic lupus erythematosus;
• History of endometrial hyperplasia (see below);
• Epilepsy;
• Asthma;
• Otosclerosis.
Reasons for immediate discontinuation of therapy
Therapy should be discontinued immediately if contraindications occur or the following conditions occur:
• Jaundice or impaired liver function;
• Significant increase in blood pressure;
• New migraine-like headache attack;
• Pregnancy.
Endometrial hyperplasia and carcinoma
• In women with an intact uterus, the risk of endometrial hyperplasia and cancer is increased when estrogen is given alone for prolonged periods. The reported increased risk of endometrial cancer among patients treated with estrogen alone is 2 to 12. times higher than in non-users, depending on the duration of treatment and the dose of estrogen (see section 4.8). After stopping treatment, the risk may remain elevated for at least 10 years.
• Adding a progestogen cyclically for at least 12 days per month / 28 days per cycle or continuous combined estrogen-progestogen therapy in non-hysterectomised women prevents the excess risk associated with estrogen-only HRT.
• During the first months of treatment, breakthrough bleeding and spotting may occur. If these appear after some time from the beginning of therapy or continue after its interruption, the reasons must be sought, also resorting to an endometrial biopsy, to exclude a malignant neoplasm of the endometrium.
Breast cancer
The general evidence suggests an increased risk of breast cancer in women who are taking combined estrogen-progestagen and possibly estrogen-only HRT, depending on the duration of taking HRT.
The randomized, placebo-controlled study Women's Health Initiative (WHI) and epidemiological studies have reported an increased risk of breast cancer in women taking estrogen-progestagen combinations for HRT which becomes evident after approximately 3 years (see section 4.8).
The excess risk becomes evident within a few years of use, but returns to initial levels after a few years (at most 5) after discontinuation of treatment.
HRT, especially combined estrogen-progestogen treatment, increases the density of mammography images which may adversely interfere with the radiological detection of breast cancer.
Ovarian cancer
Ovarian cancer is much rarer than breast cancer. Long-term use (at least 5-10 years) of estrogen-only HRT products has been associated with a slightly increased risk of ovarian cancer (see section 4.8). Some studies, including the WHI trial, suggest that Long-term use of combined HRTs may confer a similar or slightly lower risk (see section 4.8).
Venous thromboembolism :
• Hormone replacement therapy (HRT) is associated with a 1.3 to 3-fold risk of developing venous thromboembolism (VTE), ie deep vein thrombosis or pulmonary embolism. A similar event is more likely to occur in the former. year of HRT compared to subsequent years (see section 4.8).
• Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. Therefore HRT is contraindicated in these patients (see section 4.3).
• Generally recognized risk factors for VTE include: use of estrogen, older age, major surgery, prolonged immobility, obesity (BMI> 30 kg / m2), pregnancy / postpartum period, systemic lupus erythematosus (SLE) and cancer. There is no unanimous opinion on the possible role played by varicose veins in VTE.
• As with all postoperative patients, prophylactic measures should be considered to avoid VTE after surgery. If elective surgery is to be followed by prolonged immobilization, it is recommended that HRT be temporarily discontinued by 4 to 6 weeks prior Treatment should not be resumed until the woman has been fully mobilized.
• For women with no personal history of VTE but with a first degree relative with a history of thrombosis at a young age, screening may be proposed after careful evaluation of its limitations (screening allows to identify only a part of the thrombophilic defects ).
If a thrombophilic defect related to thrombosis is identified in family members or if the defect is 'severe' (eg antithrombin, protein S or protein C deficiencies or a combination of defects) HRT is contraindicated.
• Women already being treated with chronic anticoagulant therapy should undergo a "careful evaluation of the benefits and risks of using HRT."
• If venous thromboembolism occurs after initiation of therapy, the drug should be discontinued. Patients should be advised of the need to contact their treating physician immediately if they have symptoms that may suggest a thromboembolic event (eg painful swelling in one leg, sudden chest pain, dyspnoea).
Coronary heart disease (CAD)
There is no evidence from randomized controlled trials of protection against myocardial infarction in women with or without existing coronary artery disease who have received combined estrogen-progestagen or estrogen-only HRT. The relative risk of coronary artery disease while using a Combined estrogen-progestogen HRT is slightly increased. Since the absolute risk of CHD at baseline is highly age-dependent, the number of additional CHD cases due to estrogen-progestogen use is very low in healthy women near menopause, but increases with advancing age. .
Ischemic stroke
Combined estroprogen therapy and estrogen-only therapy are associated with a 1.5-fold increased risk of ischemic stroke. The relative risk does not vary with age or with the time since menopause. However, as the baseline risk of stroke is highly age-dependent, the overall risk of stroke in women who use HRT increases with age (see paragraph 4.8).
Other conditions :
• Since the intake of estrogen can lead to fluid retention, patients with impaired renal or cardiac function should be carefully monitored.
• Women with pre-existing hypertriglyceridaemia should be closely monitored during estrogen or hormone replacement therapy, as rare cases of significant increases in plasma triglycerides resulting in pancreatitis have been reported in this condition during estrogen therapy.
• Estrogen increases thyroid-binding globulin (TBG), which leads to an increase in circulating total thyroid hormone, measured as protein-bound iodine (PBI), in T4 levels (measured by column chromatography or radioimmunoassay ) or T3 levels (measured by radioimmunoassay). Resin uptake of T3 is reduced as it reflects the increase in TBG. Free T4 and T3 concentrations are unaffected. Other binding proteins may be increased in serum. ie corticosteroid-binding globulin (CBG), sex hormone binding globulin (SHBG), resulting in increased plasma concentrations of corticosteroids and sex hormones, respectively. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen / substrate renin, alpha-I-antitrypsin, ceruloplasmin).
• Estrogen can induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema.
• The use of HRT does not improve cognitive function. There is some evidence of an increased risk of probable dementia in women who start continuous combined or estrogen-only HRT after the age of 65.
Lactose
Due to the presence of lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose or galactose malabsorption should not take this medicine.
Cochineal red
The presence of cochineal red (E124) can cause allergic reactions.
04.5 Interactions with other medicinal products and other forms of interaction
The metabolism of estrogens and progestogens may increase with concomitant intake of substances known to induce drug metabolising enzymes, particularly those of cytochrome P450, such as antiepileptics (eg phenobarbital, phenytoin, carbamazepine) and anti-infectives (rifampicin, rifabutin , nevirapine, efavirenz).
The simultaneous intake of rifampicin reduces the bioavailability of nomegestrol acetate by 91% and increases that of estradiol by 28%.
Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones.
Herbal preparations containing St. John's wort (Hypericum perforatum) can induce the metabolism of estrogen and progestin.
From a clinical point of view, an increased metabolism of estrogens and progestogens can reduce their efficacy and lead to changes in menstrual cycles.
04.6 Pregnancy and breastfeeding
Pregnancy
NAEMIS is not indicated during pregnancy. If pregnancy is ascertained while taking NAEMIS, the drug should be stopped immediately.
Clinically, data on a limited number of exposed pregnancies indicate no adverse effects of nomegestrol acetate on the fetus.
The results of most epidemiological studies relating to accidental exposure of the fetus to oestrogens or to estrogen-progestagenic associations do not indicate to date neither teratogenic nor foetotoxic effects.
Feeding time
NAEMIS is not indicated during lactation.
04.7 Effects on ability to drive and use machines
NAEMIS does not affect the ability to drive and use machines.
04.8 Undesirable effects
The frequency of adverse events is classified as follows: very common (≥ 1/10), common (≥ 1/100 to uncommon (≥ 1/1000 to
During phase III and IV clinical trials, very common (≥ 10%) undesirable effects were mastodynia, spotting and intercurrent bleeding. These effects are usually seen during hormonal treatment of menopause.
The adverse drug reactions listed in the table below emerged in NAEMIS phase III clinical trials and occur in less than 10% of cases:
Breast Cancer Risk
• A doubling of the risk of being diagnosed with breast cancer has been reported in women taking combined estroprogen therapy for more than 5 years.
• Any increased risk in patients treated with estrogen-only therapy is substantially less than that observed in patients using estrogen-progestogen combinations.
• The level of risk depends on the duration of use (see section 4.4).
• The results of the largest randomized placebo-controlled study (WHI study) and the largest epidemiological study (MWS) are presented below.
Million Women study (MWS) - Estimated additional risk of 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 did not use HRT prior to the study, there was no evidence of any increased risk during the first 5 years of treatment: after 5 years, the risk was greater than in women who did not have made use of a TOS.
* WHI study in women with no uterus, which did not demonstrate an increased risk of breast cancer
Endometrial cancer risk
Postmenopausal women with a uterus
The risk of endometrial cancer is about 5 in every 1,000 women with a uterus who are not using HRT.
In women with a uterus, the use of estrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4).
Depending on the duration of treatment and the dose of estrogen, in the case of estrogen-only therapy, the increased risk of endometrial cancer in epidemiological studies ranged from 5 to 55 additional cases diagnosed per 1,000 women between 50 and 65 years of age.
Adding a progestogen to estrogen-only therapy for at least 12 days per cycle can prevent this increased risk.In the Million Women Study, the use of combined (sequential or continuous) HRT for five years did not increase the risk of endometrial cancer (RR of 1.0 (0.8-1.2)).
Ovarian cancer risk
Long-term use of estrogen-only and combined estrogen-progestagen HRT has been associated with a slightly increased risk of ovarian cancer. In the Million Women Study, 5 years of HRT resulted in 1 additional case in every 2,500 patients. .
Risk of venous thromboembolism
HRT is associated with a 1.3 to 3-fold increased relative risk of developing venous thromboembolism (VTE), ie deep vein thrombosis or 'pulmonary embolism. use of HRT (see section 4.4) The results of the WHI studies are presented below:
WHI Studies - Additional risk of VTE when used for 5 years
Coronary heart disease risk
The risk of coronary heart disease is slightly increased in patients over 60 years of age treated with combined estrogen-progestagen HRT (see section 4.4).
Risk of ischemic stroke
• The use of estrogen-only and estrogen-progestagen therapy is associated with a 1.5-fold increased relative risk of ischemic stroke. The risk of haemorrhagic stroke is not increased during HRT use.
• The relative risk is not dependent on age or duration of use, but because the baseline risk is highly age-dependent, the overall risk of stroke in women taking HRT increases with age; see section 4.4.
WHI studies combined - Additional risk of ischemic stroke * when used for 5 years
Other adverse reactions associated with estrogen-progestogen treatment have been reported:
• cholecystopathy;
• 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
The reporting of suspected adverse reactions that occur after the 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 Italian Medicines Agency Website : www.aifa.gov.it/responsabili
04.9 Overdose
Overdose is manifested by breast tenderness, abdominal-pelvic swelling, irritability, nausea, vomiting and / or metrorrhagia. There is no antidote, but symptomatic therapies can be administered.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: progestogens and estrogens for sequential administration.
ATC code: G03FB (genitourinary system and sex hormones).
NAEMIS is a cyclic, non-contraceptive, estrogen-progestogen combination that contains estradiol and nomegestrol acetate.
Estradiol
the active ingredient 17b-estradiol is chemically and biologically identical to the endogenous human estradiol. It replaces the loss in estrogen production in menopausal women and relieves the symptoms of menopause.
Nomegestrol acetate
nomegestrol acetate is a synthetic progestin, derived from 19nor-progesterone. It has no androgenic and estrogenic activity and its affinity with the progesterone receptor is 2.5 times that of the natural hormone.
Because estrogen stimulates endometrial growth, estrogen alone increases the risk of endometrial hyperplasia and cancer. Nomegestrol acetate greatly reduces the risk of estrogen-induced endometrial hyperplasia in non-hysterectomised women.
The addition of nomegestrol acetate, in the second phase of the treatment, induces withdrawal bleeding.
The improvement in menopause symptoms begins during the first few weeks of treatment.
Regular withdrawal bleeding occurs in 93% of treatment cycles with a mean duration of 4.7 days. Withdrawal bleeding usually begins 4 days after the last tablet of the progestogen phase.
Intermenstrual bleeding and / or spotting occurs in 12.7% of women during the first three months of treatment and in 10.6% during the last three months of treatment. Amenorrhea (no bleeding or spotting) occurs in 0.6% of women during the first year of treatment.
05.2 Pharmacokinetic properties
The combination of 17b-estradiol and nomegestrol acetate does not significantly alter the bioavailability of both active ingredients, compared to separate intake. The administration of the combination of 17b-estradiol and nomegestrol acetate leads to an increase of about 25% in the maximum concentration of estradiol and 36% in that of nomegestrol compared to the separate administration of the two products. Absorption occurs quickly with a Observed Tmax of approximately 1 hour for estradiol and 2 hours for nomegestrol acetate.
The steady state pharmacokinetic profile of estradiol and nomegestrol acetate is as follows:
Estradiol:
• minimum concentration (Cmin) 43 ± 4.8 pg / ml;
maximum concentration (Cmax) 290 ± 32.7 pg / ml and mean (C mean) 72 ± 5.6 pg / ml;
• area under the curve 2765 ± 270.0 pg.h / ml.
Nomegestrol acetate:
• minimum concentration (Cmin) 6.5 ± 0.40 ng / ml;
maximum concentration (Cmax) 20.4 ± 1.00 ng / ml and mean (Cmedia): 8.6 ± 0.4 ng / ml;
• area under the curve 630.3 ± 41.64 ng.h / ml-
05.3 Preclinical safety data
Animal studies with estradiol and nomegestrol acetate alone or in combination have shown the expected estrogen and gestagenic effects. Reproductive toxicity, genotoxicity or carcinogenicity studies have not been conducted with the combination estradiol and nomegestrol acetate. Estradiol exhibited embryo-fetal effects at relatively low doses. Nomegestrol acetate is neither genotoxic nor teratogenic.
There are no other preclinical data relevant to prescribing.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Pink tablet:
Povidone (K25 or K 30)
Lactose monohydrate
Microcrystalline cellulose
Glycerol distearate
Anhydrous colloidal silica
Crospovidone
Cochineal red A (E124), aluminum lake.
White tablet:
Povidone (K25 or K30)
Lactose monohydrate
Microcrystalline cellulose
Glycerol distearate
Anhydrous colloidal silica
Crospovidone.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
18 months.
06.4 Special precautions for storage
Do not store above 25 ° C.
Store in the original package to protect from moisture.
06.5 Nature of the immediate packaging and contents of the package
Each blister (PVC / PE / ACLAR / Aluminum) contains 10 pink and 14 white tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Unused Naemis tablets should not be disposed of via wastewater or the municipal sewage system. The active hormone compounds in the tablet can have harmful effects if they reach the aquatic environment. They should be returned to a pharmacy or disposed of in another safe way, according to local regulations. These measures will help protect the environment.
07.0 MARKETING AUTHORIZATION HOLDER
ratiopharm Italia S.r.l. - Piazzale Luigi Cadorna, 4 -20123 Milan
08.0 MARKETING AUTHORIZATION NUMBER
AIC n. 036163018
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
12.11.2004
10.0 DATE OF REVISION OF THE TEXT
February 2016
