PERIFEM 2 mg/10 mg TABLETS

Introduction

Package Leaflet: Information for the User

Perifem 2 mg/10 mg tablets

estradiol valerate, medroxyprogesterone acetate

Read this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

1. What Perifem 2 mg/10 mg tablets are and what they are used for
2. What you need to know before you take Perifem 2 mg/10 mg tablets
3. How to take Perifem 2 mg/10 mg tablets
4. Possible side effects
5. Storing Perifem 2 mg/10 mg tablets
6. Contents of the pack and other information

1. What Perifem 2 mg/10 mg tablets are and what they are used for

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

They are used for:

Relief of symptoms occurring after menopause

During menopause, the amount of estrogen produced by the female body decreases. This can cause symptoms such as hot flushes, night sweats, and genital itching. Perifem relieves these post-menopausal symptoms. You will only be prescribed Perifem if your symptoms are severe enough to affect your daily life.

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

This medicine should not be used to prevent heart disease or to improve memory.

Perifem is not a contraceptive and does not restore fertility.

2. What you need to know before you take Perifem 2 mg/10 mg tablets

Medical history and regular check-ups

HRT carries risks that need to be considered when deciding whether to start or continue HRT.

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

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

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

Have 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 conditions apply to you. Consult your doctorbefore taking Perifem if you are not sure about any of the following:

• if you have or have had breast canceror if you suspect you may have it
• if you have cancer that is sensitive to estrogens, such as cancer of the lining of the uterus (endometrium), or if it is suspected
• if you have unexplained vaginal bleeding
• if you have excessive thickening of the lining of the uterus (endometrial hyperplasia)for which you are not receiving treatment
• if you have or have had a blood clot in a vein(thrombosis), such as in the legs (deep vein thrombosis) or lungs (pulmonary embolism)
• if you have a blood clotting disorder (such as lack of protein C, protein S, or antithrombin)
• if you have or have had a disease caused by blood clots in the arteries, such as a heart attack, stroke, or angina

• if you have or have had any liver disorderand liver function tests have not returned to normal
• if you have a rare blood disorder called porphyria (a genetic disorder)
• if you are allergic(hypersensitive) to estradiol valerate, medroxyprogesterone acetateor any of the other ingredients of this medicine (listed in section 6)
• if you are pregnant or think you may be pregnant.

If any of these conditions appear for the first time while taking Perifem, stop taking it immediately and consult your doctor.

Warnings and precautions

Before starting treatment, tell your doctor if you have ever had any of the following problems, as they may return or worsen during treatment with Perifem. In this case, you should see your doctor more often for check-ups.

• uterine fibroids
• endometriosis or a history of excessive thickening of the lining of the uterus (endometrial hyperplasia)
• increased risk of blood clots (see "Blood clots in a vein (thrombosis)")
• increased risk of 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
• systemic lupus erythematosus (SLE)
• epilepsy
• asthma
• otosclerosis (a condition affecting the middle ear)
• very high levels of triglycerides in the blood
• fluid retention due to heart or kidney problems
• hereditary or acquired angioedema

You should see your doctor immediately if you think you may be pregnant while taking Perifem.

Stop taking Perifem and see your doctor immediately

If you notice any of the following while taking HRT:

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

• painful swelling and redness of the legs
• sudden chest pain
• difficulty breathing

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

Note:Perifem is not a contraceptive. If it has been less than 12 months since your last menstrual period or you are under 50 years old, you may still need to use contraception to prevent pregnancy. Ask your doctor for advice.

Hormone Replacement Therapy and cancer

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

Treatment with estrogen-only HRT will increase the risk of excessive thickening of the lining of the uterus (endometrial hyperplasia) and cancer of the lining of the uterus (endometrial cancer).

The progestogen in Perifem protects you from this additional risk.

Unexpected bleeding

While taking Perifem, you will have a monthly bleed (also called withdrawal bleeding).

See your doctor as soon as possibleif you have unexpected bleeding or spotting in addition to your monthly bleed that:

• continues after the first 6 months
• starts after you have been taking Perifem for more than 6 months
• continues after you stop taking Perifem

Breast cancer

The use of HRT with combined estrogen-progestogen or estrogen-only therapy increases the risk of breast cancer. The additional risk depends on how long you take HRT. The additional risk becomes apparent after 3 years of use. After stopping HRT, the additional risk will decrease over time but 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 taking HRT, 13-17 out of every 1000 women will be diagnosed with breast cancer over a 5-year period.

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

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

In women aged 50-59 who are not taking HRT, 27 out of every 1000 women will be diagnosed with breast cancer over a 10-year period.

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

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

Regular breast checks. See 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

In addition, it is recommended to participate in a regular mammography screening program. For mammography screening, it is important to inform the nurse or healthcare professional taking the X-rays that you are taking HRT, as this medication may increase breast density and affect the results of the mammogram. When breast density increases, it may be more difficult to detect lumps in the mammogram.

Ovarian cancer

Ovarian cancer is less common than breast cancer. The use of HRT with estrogen-only or combined estrogen-progestogen therapy has been associated with a slightly increased risk of ovarian cancer.

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

Effect of HRT on the heart and circulation

Blood clots in a vein (thrombosis)

The risk of having a blood clot in the veins is approximately 1.3-3 times higher in HRT users than in non-users, especially during the first year of use.

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

You are more likely to have a blood clot in the veins as you get older and if any of the following apply to you.

Tell your doctor if you have any of these conditions:

• you are unable to walk for a long time due to a major surgery, injury, or illness (see section 3, If you need to have surgery)
• you are severely overweight (body mass index >30 kg/m2)
• you have a blood clotting disorder 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 leg, lung, or other organ
• if you have systemic lupus erythematosus (SLE)
• if you have cancer

For more information on the symptoms of a blood clot, see "Stop taking Perifem and see your doctor immediately".

Comparison

On average, over a 5-year period, 4-7 out of every 1000 women aged 50-59 who are not taking HRT will have a blood clot in the veins.

Among women aged 50-59 who take combined estrogen-progestogen HRT for more than 5 years, there will be 9-12 cases per 1000 users (i.e., 5 additional cases).

Heart disease (heart attack)

There is no evidence that HRT prevents heart attacks.

Women over 60 years old who use combined estrogen-progestogen HRT have a slightly higher risk of heart disease than those who do not take HRT.

Stroke

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

Comparison

Among women aged 50 who are not taking HRT, on average, 8 out of every 1000 women will have a stroke over a 5-year period.

Among women aged 50 who take HRT, there will be 11 cases per 1000 users over a 5-year period (i.e., 3 additional cases).

Other warnings

• HRT will not prevent memory loss. There is some evidence that memory loss is more common in women who start HRT after the age of 65. Ask your doctor for advice.

You should discuss the possible alternatives to HRT and the duration of treatment with your doctor. This should be reviewed regularly throughout your treatment.

• Perifem does not restore fertility.

Other medicines and Perifem 2 mg/10 mg tablets

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. Your doctor will advise you.

Some medicines may interact with Perifem and affect its efficacy. This may cause irregular bleeding. It is especially important to tell your doctor if you are going to use or are using any of the following medicines:

• Medicines for epilepsy(such as phenobarbital, phenytoin, and carbamazepine).
• Medicines for tuberculosis(such as rifampicin, rifabutin).
• Medicines for HIV(such as nevirapine, efavirenz, ritonavir, and nelfinavir).
• Herbal remedies containing St. John's Wort(Hypericum perforatum).
• The anti-inflammatory medicine (phenylbutazone).
• Antibiotics and other anti-infective medicines (such as erythromycin, ketoconazol).
• Certain anti-ulcer medicines (such as cimetidine).

HRT may affect the way other medicines work:

• A medicine for epilepsy (lamotrigine), as it may increase the frequency of seizures.
• Medicines for hepatitis C (such as the combination of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, as well as a regimen with glecaprevir/pibrentasvir) may cause increases in liver function test results (increase in liver enzyme ALT) in women using HRT that contains ethinylestradiol. Perifem 2 mg/10 mg tablets contain estradiol instead of ethinylestradiol. It is not known whether liver enzyme ALT may increase when using Perifem 2 mg/10 mg tablets with this hepatitis C regimen.

Laboratory tests

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

Children

Perifem should not be used in children.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Perifem is only intended 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 using machines

This medicine does not affect your ability to drive or use machines.

Perifem 2 mg/10 mg tablets contain lactose

If your doctor has told you that you have an intolerance to some sugars, contact them before taking this medicine.

3. How to take Perifem 2 mg/10 mg tablets

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 necessary time. 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 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 posology is adjusted to the calendar pack.

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

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

1. The tablets are taken in the sequence indicated by the numbers on the blister, first the white tablets and then the blue ones. Afterwards, 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.

1. 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 interval (usually about 10% of patients) or that it only appears in some cycles.

If you are going 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 (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

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

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

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

Do not take a double dose to make up for forgotten doses.

It is preferable to take the tablets at night. In case of forgetting a dose, take it the next morning and take the tablet for the day normally at night. If you completely forget to take a tablet for a whole day, continue with the next one. A small bleeding may appear later during the cycle.

4. Possible side effects

Like all medications, this medication can cause side effects, although not all people experience them, especially during the first months of treatment. They are usually mild and decrease over time.

The following diseases have been reported more frequently in women using HRT than in women not using HRT:

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

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 flashes
• nausea
• vomiting
• digestive disorders (stomach pain, flatulence)
• irregular vaginal bleeding
• vaginal discharge
• changes in the cycle
• edema (swelling)
• sweating

Uncommon 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 coagulation factors
• anxiety
• insomnia
• apathy
• emotional lability
• changes in concentration
• changes in libido (sexual desire)
• mood changes
• migraine (headaches)
• tremors
• vertigo
• vision changes
• constipation
• diarrhea
• acne
• hair loss
• dry skin
• skin redness (erythema)
• itching
• joint disorders
• muscle cramps
• increased number of urinations and/or urgent urination
• breast enlargement
• increased thickness of the uterine walls (endometrial hyperplasia)
• fatigue

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

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 disease
• various skin disorders:

• skin discoloration, especially on the face or neck, known as "pregnancy mask" (chloasma)
• red and painful nodules on the skin (erythema nodosum)
• red rash in the form of a target or sores (erythema multiforme)

Reporting 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 the Spanish Medicines Surveillance System: https://www.notificaram.es. By reporting side effects, you can contribute to providing more information on the safety of this medication.

5. Storage of Perifem 2 mg/10 mg tablets

Keep this medication out of 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 that appears on the packaging after CAD. The expiration date is the last day of the month indicated.

Medications should not be thrown down the drain or into the trash. Deposit the packaging and medications you no longer need at the SIGRE point in the pharmacy. In case of doubt, ask your pharmacist how to dispose of the packaging and medications you no longer need. This way, you will help protect the environment.

6. Package contents and additional information

Composition of Perifem 2 mg/10 mg tablets

White tablets:

• The active ingredient is estradiol valerate, 2 mg.
• The other ingredients are lactose, cornstarch, gelatin, talc, and magnesium stearate.

Blue tablets:

• The active ingredients are estradiol valerate, 2 mg, and medroxyprogesterone acetate, 10 mg.
• The other ingredients are lactose, cornstarch, indigotine (E-132), gelatin, povidone, talc, and magnesium stearate.

Appearance of the product and package contents

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

Marketing authorization holder

Orion Corporation

Orionite 1

FI-02200 Espoo

Finland

Manufacturer

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

You can request more information about this medication by contacting the local representative of the marketing authorization holder:

Orion Pharma, S.L.

Phone: +349 159 9 86 01

Date of the last revision of the leaflet: August 2023

Detailed and updated information on this medication is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es