Package Insert: Information for the User

Perifem 2 mg/10 mg Tablets

Valerato of estradiol, medroxiprogesterona acetate

Read this package insert carefully before starting to take this medication, as it contains important information for you.

• Keep this package insert, as you may need to refer to it again.
• If you have any questions, consult your doctor or pharmacist.
• This medication has been prescribed only for you, and you should not give it to others who have the same symptoms as you, as it may harm them.
• If you experience any adverse effects, consult your doctor or pharmacist, even if they are not listed in this package insert. See section 4.

Perifem 2 mg/10 mg tablets is a Hormone Replacement Therapy (HRT).It contains two types of female hormones, an estrogen and a progestogen.

It is used for:

Relief of symptoms that appear after menopause

During menopause, natural or surgically induced, the amount of estrogen produced by the woman's body decreases. This can cause symptoms such as hot flashes in the face, neck, and chest ("hot flashes"), night sweats, urogenital disorders (vulvovaginitis atrophy). Perifem relieves postmenopausal symptoms. Only your doctor will prescribe Perifem if your symptoms truly interfere with your daily life.

Perifem imitates the female menstrual cycle; the first estrogen phase (11 days; white tablets) is followed by a phase of combined estrogen-progestogen (10 days; blue tablets), resulting in normal withdrawal bleeding usually during the following week.

This medication should not be used to prevent heart disease or to increase intellectual capacity.

Perifem is not a contraceptive, nor does it restore fertility.

Medical History (Background) and Regular Check-ups

The HRT involves risks that need to be taken into account when deciding whether to start or continue taking it.

The experience in treating women with premature menopause (due to ovarian failure or surgically induced) is limited. If you have premature menopause, the risks of using HRT may be different. Consult your doctor.

Before starting(or restarting)with HRT, your doctor will ask you a series of questions about your personal and family medical history. Your doctor may consider it appropriate to perform a physical examination.This physical examination may include a breast examination and an internal examination, if necessary.

Once you have started treatment with Perifem, you should visit your doctor for regular check-ups (at least once a year). In these check-ups, discuss with your doctor the benefits and risks of continuing Perifem.

Undergo regular breast checks, as recommended by your doctor.

Do not take Perifem 2 mg/10 mg tablets

Do not take Perifem if any of the following circumstances apply.Consult your doctorbefore taking Perifem if you are unsure about some of the points described below:

• if you have or have hadbreast canceror if you suspect you may have it
• if you have atype of cancer that is sensitive to estrogen, such as endometrial cancer, or if you suspect you may have it
• if you haveunexplained vaginal bleeding
• if you haveanexcessive thickening of the uterine lining (endometrial hyperplasia)for which you are not receiving treatment
• if you have or have hadblood clots in a vein(thrombosis) such as in the legs (deep vein thrombosis) or lungs (pulmonary embolism)
• if you have ablood clotting disorder(such as a deficiency of protein C, protein S, or antithrombin)
• if you have or have hadarterial disease caused by blood clots, such as a heart attack, stroke, angina, or retinal artery disease

• if you have or have hadliver diseaseand liver function tests have not returned to normal
• if you have a rare blood disorder calledporphyria(a disorder of a blood pigment) that is inherited
• if you areallergic(hypersensitive) tovalerianate of estradiol, medroxyprogesterone acetateor to any of the other components of this medication (including those listed insection 6)
• if you are pregnant or suspect you may be pregnant.

If any of the situations mentioned above occur for the first time while taking Perifem, stop taking it immediately and consult your doctor immediately.

Warnings and Precautions

Before starting treatment, inform your doctor if you have ever had any of the following problems, as they may recur or worsen during Perifem treatment. In that case, you should visit your doctor more frequently for check-ups.

• uterine fibroids
• growth of the uterine lining outside the uterus (endometriosis) or a history of excessive growth of the uterine lining (endometrial hyperplasia)
• increased risk of blood clots in the veins (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 disorders,such as a benign liver tumor
• diabetes
• gallstones
• migraines or severe headaches
• autoimmune disease that affects many parts of the body (systemic lupus erythematosus, SLE)
• epilepsy
• asthma
• disease affecting the eardrum and ear (otosclerosis)
• very high levels of fat in the blood (triglycerides)
• fluid retention due to heart or kidney problems
• hereditary or acquired angioedema

You should visit your doctor immediately if you think you may be pregnant while usingPerifem.

Stop taking Perifem and visit your doctor immediately

If you notice any of the following situations while taking HRT:

• any of the conditions mentioned in the section "Do not take Perifem 2 mg/10 mg tablets"
• yellowing of the skin or white of the eyes (jaundice). This may be a sign of liver disease
• swelling of the face, tongue, and/or throat and/or difficulty swallowing or urticaria, along with difficulty breathing, which are indicative of angioedema
• a significant increase in blood pressure (the symptoms may include headache, fatigue, dizziness)
• migraine-like headaches that occur for the first time
• if you become pregnant
• if you notice symptoms of a blood clot in the blood, such as:

• painful and swollen legs
• sudden chest pain
• difficulty breathing

For more information, see "Blood clots in a vein (thrombosis)".

Note:Perifem is not a contraceptive. If you have had less than 12months since your last menstrual period or are less than 50years old, it is possible that you may still need to use contraceptive measures to prevent pregnancy. Ask your doctor.

Hormone Replacement Therapy and Cancer

Excessive thickening of the uterine lining (endometrial hyperplasia) and endometrial cancer

Treatment withestradiol alone in HRT will cause an increase in therisk of excessive thickening of the uterine lining (endometrial hyperplasia) and endometrial cancer.

The progestogen in Perifem protects you from this additional risk.

Unexpected bleeding

While taking Perifem, you will have a bleeding (bleeding) once a month (also called bleeding due to withdrawal).

Visit your doctor as soon as possibleif you have unexpected bleeding or spots of blood (spotting) in addition to the monthly bleeding, which:

• continues after the first 6 months
• starts after having taken Perifem for more than 6months
• continues after stopping Perifem

Breast cancer

The available data show that the use of hormone replacement therapy (HRT) with estrogen-progestogen combinations or with estrogen alone increases the risk of breast cancer. The additional risk depends on the duration of HRT use. The additional risk becomes apparent after 3 years of use. After stopping HRT, the additional risk will decrease over time, but the risk may persist for 10 years or more if you have used HRT for more than 5 years.

Comparison

In women aged 50-54 who are not using HRT, on average, 13-17 out of every 1000 will be diagnosed with breast cancer in a 5year period.

In women aged 50 who start HRT with estrogen alone for 5 years, there will be between 16 and 17 cases per 1000 users (i.e., between 0 and 3 additional cases).

In women aged 50 who start HRT with estrogen-progestogen for 5 years, there will be between 21cases per 1000 users (i.e., between 4- 8cases).

In women aged 50-59 who are not taking HRT, on average, 27 cases of breast cancer per 1000 women will be diagnosed in a 10year period.

In women aged 50 who start HRT with estrogen alone for more than 10 years, there will be 34 cases per 1000 users (i.e., 7 additional cases).

In women aged 50 who start HRT with estrogen-progestogen for 10years, there will be 48 cases per 1000 users (i.e., 21 additional cases).

Regular breast check-ups. Consult your doctor if you notice any changes such as:

• dimpling of the skin

• changes in the nipple

• any lump that you can see or feel

It is also recommended to join a regular mammography screening program. For the mammography check-up, it is essential to inform the nurse or healthcare professional taking the X-rays that you are using HRT, as this medication can increase the density of your breasts and may affect the mammography result. When breast density increases, it may not be possible to detect lumps in the mammography.

Ovarian cancer

Ovarian canceris less common than breast cancer. The use of HRT with estrogen alone or with estrogen-progestogen combinations has been associated with a slightly higher risk of ovarian cancer.

The risk of ovarian cancer varies with age. For example, in women aged 50-54 who are not using HRT, there are approximately 2 cases of ovarian cancer per 2000 women in a 5year period. In women taking HRT for 5 years, there are approximately 3 cases per 2000 patients (i.e., approximately 1 additional case).

Effect of HRT on the heart and circulation

Blood clots in a vein (thrombosis)

The risk of havingblood clots in the veinsis approximately 1.3to 3times higher in HRT users than in non-users, especially during the first year of use.

Blood clots can be serious, and if one dislodges and moves to the lungs, it can cause chest pain, difficulty breathing, loss of consciousness (fainting), and even death.

It is more likely to have a blood clot in the veins as you age and if you have any of the following circumstances.

Inform your doctor if you have any of these situations:

• you cannot walk for a long time due to a major surgery, injury, or illness (see section 3, If you have to undergo surgery)
• you have significant obesity (BMI > 30Kg/m2)
• you have a blood clotting disorder that requires long-term treatment with a medication used to prevent blood clots
• any of your close relatives have had a blood clot in a vein, such as in the legs, lungs, or other organs
• you have systemic lupus erythematosus (SLE)
• you have cancer

For more information on the symptoms of blood clots in the blood, see "Stop taking Perifem and visit your doctor immediately".

Comparison

On average, in a 5year period, 4to 7out of every 1000 women aged 50 who are not using HRT will have a blood clot in the veins.

Between women aged 50 who are using HRT, there will be 9to 12cases per 1000 users (i.e., 5additional cases).

Cardiac disease (myocardial infarction)

There is no evidence that HRT prevents myocardial infarction.

Women over 60years old who use HRT have a slightly higher risk of developing cardiac disease than those who do not use HRT.

Stroke (apoplexy)

The risk of stroke is 1.5times higher in HRT users than in non-users. The number of additional stroke cases due to HRT use will increase with age.

Comparison

On average, in a 5year period, 8out of every 1000 women aged 50 who are not using HRT will have a stroke.

Between women aged 50 who are using HRT, there will be 11cases per 1000 users (i.e., 3additional cases).

Other warnings

• HRT will not prevent memory loss. There are some indications that memory loss is more common in women who start HRT after 65years old. Ask your doctor.

You should discuss with your doctor the possible alternative treatments available for your specific situation and how long the treatment should be prolonged. This should be reviewed regularly throughout the treatment.

• Perifem does not restore fertility.

Other medications and Perifem 2 mg/10 mg tablets

Inform your doctor or pharmacist if you are taking, have taken recently, or may need to take any other medication.Your doctor will advise you.

Some medications may interact with Perifem and modify its effect. This could cause irregular bleeding. It is especially important to inform your doctor if you plan to use or are using any of the following medications:

• Medications forepilepsy(such as phenobarbital, phenytoin, and carbamazepine).
• Medications fortuberculosis(such as rifampicin, rifabutin).
• Medications forHIV infection(such as nevirapine, efavirenz, ritonavir, and nelfinavir).
• Preparations based on medicinal plants containingSt. John's Wort(Hypericum perforatum).
• Anti-inflammatory medication (phenylbutazone).
• Antibiotics and other anti-infective medications (such as erythromycin, ketoconazole).
• Some anti-ulcer medications (such as cimetidine).

HRT may affect the way some other medications work:

• A medication for epilepsy (lamotrigine), as it may increase the frequency of seizures.
• Medications for hepatitis C virus (HCV) (such as the combination regimen of ombitasvir / paritaprevir/ritonavir with or without dasabuvir, as well as a regimen with glecaprevir/pibrentasvir) may cause increases in liver function test results (elevated ALT levels) in women using HRT that contain ethinylestradiol.Perifem 2 mg/10mg tabletscontains estradiol instead of ethinylestradiol. It is not known whether an increase in ALT levels can occur when usingPerifem 2 mg/10mg tabletswith this HCV combination regimen.

Laboratory tests

If you need to have a blood test, inform your doctor or the laboratory staff that you are taking Perifem, as this medication may alter the results of some tests.

Children

Perifem should not be used in children.

Pregnancy and lactation

If you are pregnant or breastfeeding, or think you may be pregnant, consult your doctor or pharmacist before using this medication.

Perifem is only indicated for postmenopausal women. If you become pregnant, stop taking Perifem and contact your doctor.

Do not use Perifem if you are pregnant or want to become pregnant.

Do not use Perifem if you are breastfeeding.

Driving and operating machinery

This medication does not affect your ability to drive or operate machinery.

Perifem 2 mg/10 mg tablets contain lactose

If your doctor has told you that you have a intolerance to certain sugars, consult with them before taking this medication.

Follow exactly the administration instructions of this medication as indicated by your doctor. In case of doubt, consult your doctor again.Your doctor will try to prescribe the lowest dose to treat your symptoms and for the shortest time necessary. Consult your doctor if you think this dose is too strong or not strong enough for you.

• If you do not have menstruation, you can start taking this medication immediately.
• If you change from another hormonal preparation, your doctor will indicate when to start the treatment with this medication.

The recommended dose is one tablet per day in cycles of 21 days and a 7-day break between packs. The dosage is adjusted according to the calendar pack.

1. In the center of each blister, you will find areas to mark the start of treatment.

When you start taking the tablets, punch the place that indicates the day of the week when you take the first tablet. This way, it is easy to control if you have taken all the tablets correctly according to the schedule. Tablets 8 and 15 are taken on the same day of the week as the first tablet.

2. The tablets are taken in the sequence indicated by the numbers on the blister, first the white tablets and then the blue ones. Then, you must take a 7-day break without taking tablets. During this time, most women experience bleeding similar to menstruation, which usually starts 2-3 days after stopping the tablets and lasts 3 to 5 days.

3. Start a new cycle of Perifem after the break on the same day of the week as the previous treatment.

It is possible that some women do not experience bleeding during the 7-day break (usually 10% of patients) or that it only appears in some cycles.

If you have to undergo surgery (operation)

If you are going to undergo surgery, inform the surgeon that you are taking Perifem. It may be necessary to stop taking Perifem for approximately 4 to 6 weeks before the operation to reduce the risk of blood clot formation in a vein (see section 2, "Blood clots in a vein"). Ask your doctor when you can start taking Perifem again.

If you take more Perifem 2 mg/10 mg tablets than you should

Overdosing with estrogens can cause nausea, headache, and vaginal bleeding.

In case of overdose or accidental ingestion, consult your doctor or pharmacist or call the Toxicological Information Service. Phone 915 620 420, indicating the medication and the amount used.

If you forgot to take Perifem 2 mg/10 mg tablets

Do not take a double dose to compensate for the missed doses.

It is better to take the tablets at night. If you forget to take a dose, take it the next morning and take the tablet for the day at night. If you completely forget to take a tablet for an entire day, continue with the next one. You may experience a small bleeding later in the cycle.

Like all medicines, this medicine can cause side effects, although not everyone will experience them, especially during the first months of treatment. They are usually mild and decrease with the time of treatment.

The following diseases have been reported more frequently among women using THS than among women not using THS:

• breast cancer
• abnormal growth or cancer of the lining of the uterus (endometrial hyperplasia or cancer)
• ovarian cancer
• blood clots in the veins of the legs or lungs (venous thromboembolism)
• heart diseases
• stroke (apoplexy)
• probable memory loss if THS is started after the age of 65years

For more information on these side effects, see section 2.

Very common side effects (may affect more than 1 in 10 women using Perifem or other hormone replacement therapy) are:

• headache
• breast pain

Common side effects (may affect up to 1 in 10 women using Perifem or other hormone replacement therapy) are:

• weight gain
• weight loss
• depression
• nervousness
• dizziness
• hot flushes
• nausea
• vomiting
• digestive discomfort (stomach pain, flatulence)
• irregular vaginal bleeding
• vaginal discharge
• cycle alterations
• swelling (edema)
• sweating

Rare side effects (may affect up to 1 in 100 women using Perifem or other hormone replacement therapy) are:

• allergic reaction
• increased appetite
• changes in blood clotting factors
• anxiety
• insomnia
• apathy
• emotional lability
• concentration alterations
• changes in libido (sexual desire)
• mood changes
• migraine (headaches)
• tremor
• dizziness
• vision alterations
• constipation
• diarrhea
• acne
• hair loss
• dry skin
• skin redness (erythema)
• itching
• joint disorders
• muscle cramps
• increased frequency of urination and/or urinary urgency
• enlargement of the breasts
• thickening of the uterine walls (endometrial hyperplasia)
• fatigue

Also, venous thromboembolism (blood clots, which may affect up to 1 in 1000 women using Perifem or other hormone replacement therapy) has been observed as a rare side effect.

Of these side effects, irregular bleeding may occur especially in the first year of treatment.

The following side effects have been reported in other hormone replacement therapies:

• gallbladder diseases
• various skin disorders:

• skin discoloration, especially on the face or neck, known as “pregnancy mask” (cloasma)
• red, painful nodules on the skin (erythema nodosum)
• red, ring-shaped rash or sores (erythema multiforme)

Reporting of side effects

If you experience any type of side effect, consult your doctor, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through theSpanish System for Pharmacovigilance of Medicines for Human Use:https://www.notificaram.es. By reporting side effects, you can contribute to providing more information on the safety of this medicine.

Keep this medication out of the sight and reach of children.

Do not store above 25°C.

Store in the original packaging.

Do not use this medication after the expiration date shown on the packaging after CAD. The expiration date is the last day of the month indicated.

Medications should not be disposed of through drains or in the trash. Dispose of packaging and unused medications at the SIGRE collection point at the pharmacy. If in doubt, ask your pharmacist how to dispose of unused packaging and medications. By doing so, you will help protect the environment.

Composition of Perifem 2 mg/10 mg tablets

White tablets:

• The active ingredient is valerianate of estradiol, 2 mg.
• The other components are lactose, cornstarch, gelatin, talc, and magnesium stearate.

Blue tablets:

• The active ingredients are valerianate of estradiol, 2 mg, and medroxiprogesterone acetate, 10 mg.
• The other components are lactose, cornstarch, indigotin (E-132), gelatin, povidone, talc, and magnesium stearate.

Appearance of the product and content of the packaging

Perifem 2 mg/10 mg tablets are presented in packaging of 21 tablets for oral use, in a calendar blister. Each blister of 21 tablets contains 11 white tablets and 10 blue tablets.

Marketing Authorization Holder

Orion Corporation

Orionite 1

FI-02200 Espoo

Finland

Responsible for Manufacturing

Orion Corporation Orion Pharma

Orionintie 1

FI-02200 Espoo

Finland

Delpharm Lille Sas -Lys Lez Lannoy

Parc d’ Activités Roubaix-Est

22 rue de Toufflers

CS 50070

Lys Lez Lannoy 59452

France

For more information about this medication, please contact the local representative of the marketing authorization holder:

Orion Pharma, S.L.

Telephone: +349 159 9 86 01

Last review date of the leaflet: August 2023

For detailed and updated information about this medication, please visit the website of the Spanish Agency for Medicines and Medical Devices (AEMPS)http://www.aemps.gob.es