Package Insert: Information for the Patient

Zafril 2 mg Tablets EFG

dienogest

Read this entire 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 even if they 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.

1. What is Zafril and how is it used

2. What you need to know before starting to take Zafril

3. How to take Zafril

4. Possible adverse effects

5. Storage of Zafril

6. Contents of the package and additional information

Zafril is a medication for the treatment of endometriosis (painful symptoms caused by an atypical location of the uterine lining tissue). Zafril contains a hormone, the progestogen dienogest.

Do not take Zafril:

• if you have ablood clotin your veins. This can occur, for example, in the blood vessels of your legs (deep vein thrombosis) or lungs (pulmonary embolism). See also“Zafril and blood clots in veins”later;
• if you have or have had aserious arterial disease, including cardiovascular disease, such as aheart attack, astroke, or aheart diseasethat causes a decrease in blood flow (angina pectoris). See also“Zafril and blood clots in arteries”later;
• if you havediabeteswith damage to blood vessels;
• if you have or have had aserious liver disease(and liver function values have not returned to normal). Symptoms of liver disease may include yellowing of the skin and/or itching all over the body;
• if you have or have had abenign or malignant liver tumor;
• if you have or have had, or are suspected of having amalignant hormone-dependent tumor, such as breast cancer or cancer of the reproductive organs;
• if you haveunexplained vaginal bleeding;
• if you areallergicto dienogest or any of the other components of this medication (listed in section 6).

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

Warnings and precautions

Consult your doctor or pharmacist before starting to take Zafril.

You should not use any type of hormonal contraceptives (pills, patches, intrauterine system) while taking Zafril.

Zafrilis not a contraceptive. If you want to avoid pregnancy, you should use condoms or other non-hormonal contraceptive methods.

In some cases, you should be particularly careful while taking Zafril, and your doctor may need to examine you regularly. Inform your doctor if you are in any of the following situations:

• if you have ever had ablood clot(venous thromboembolism) or if a close relative has had a blood clot at a relatively early age;
• if you have a close relative who has hadbreast cancer;
• if you have ever haddepression;
• if you havehigh blood pressure (hypertension)or if you develop hypertension while taking Zafril;
• if you have aliver diseasewhile taking Zafril. Symptoms may include yellowing of the skin or eyes or itching all over the body. Also inform your doctor if you have had any of these symptoms in a previous pregnancy;
• if you havediabetesor have had temporary diabetes in a previous pregnancy;
• if you have ever hadmelasma(brownish patches on the skin, especially on the face); avoid excessive exposure to the sun or ultraviolet radiation;
• if you havelower abdominal painwhile taking Zafril.

While taking Zafril, the likelihood of becoming pregnant is reduced because this medication can affect ovulation.

If you become pregnant while taking Zafril, you have a slightly higher risk of having an ectopic pregnancy (the embryo develops outside the uterus). Inform your doctor before starting to take Zafril if you have already had an ectopic pregnancy or if you have a fallopian tube dysfunction.

Zafril and heavy menstrual bleeding

Menstrual bleeding may worsen with the use of Zafril, for example, in women with a condition in which the uterine lining (endometrium) grows into the muscular layer of the uterus known as adenomyosis uterina orbenign uterine tumors, sometimes called fibroids or uterine leiomyomas. If bleeding is intense and prolonged, it may lead to low red blood cell levels (anemia), which in some cases can be severe. In case of anemia, you should consult your doctor if you should stop taking Zafril.

Zafril and changes in menstrual pattern

Most women treated with Zafril experience changes in their menstrual cycle pattern (see section 4).

Zafril and blood clots in veins

Some studies suggest that there may be a slight increase, although not statistically significant, in the risk ofblood clots in the legs (venous thromboembolism)associated with the use of progestogen-containing medications like Zafril. In very rare cases, blood clots can cause permanent and severe disabilities or even be fatal.

The risk ofblood clots in veinsincreases:

• with age;
• if you are overweight;
• if you or a close relative has had a blood clot in the leg (thrombosis), lungs (pulmonary embolism), or another organ at a relatively early age;
• if you need to undergo surgery, if you have had a serious accident, or if you have been immobile for a prolonged period. It is essential to inform your doctor in advance that you are taking Zafril, as it may be necessary to interrupt treatment. Your doctor will tell you when to start taking Zafril again, usually about two weeks after regaining mobility.

Zafril and blood clots in arteries

There is little evidence of a relationship between progestogen-containing medications like Zafril and an increased risk of having a blood clot, for example, in the blood vessels of the heart (heart attack) or brain (stroke). In women with hypertension, these medications may slightly increase the risk of stroke.

The risk of having ablood clot in arteriesincreases:

• if you smoke. It is strongly recommended that you quit smoking while taking Zafril, especially if you are over 35 years old.
• if you are overweight;
• if a close relative has had a heart attack or stroke at a relatively early age;
• if you have high blood pressure.

Zafril and cancer

With the available data, it is not known with certainty whether Zafril increases or decreases the risk of breast cancer. It has been observed that breast cancer is slightly more common in women taking hormones compared to those not taking hormones, but it is unknown whether it is due to treatment. For example, tumors may be detected more frequently and earlier in women taking hormones because their doctor examines them more frequently. The appearance of breast tumors decreases gradually after interrupting hormone treatment.It is essential to regularly check your breastsand consult your doctor if you detect any lump.

In rare cases, benign liver tumors have been reported in women taking hormones, and in fewer cases, malignant liver tumors. Inform your doctor if you experience unusual stomach pain.

Zafril and osteoporosis

Bone mineral density (BMD) alterations

Use of Zafril may affect the bone resistance of adolescents (12 to less than 18 years). Therefore, if you are under 18 years old, your doctor will carefully evaluate the benefits and risks of taking Zafril for you as a patient, taking into account any possible risk factors for bone loss (osteoporosis).

If you take Zafril, it will be helpful for your bones to receive an adequate intake of calcium and vitamin D, either through diet or supplements.

If you have a higher risk of osteoporosis (weakening of bones due to loss of bone minerals), your doctor will carefully evaluate the risks and benefits of treatment with Zafril because Zafril causes a moderate suppression of estrogen production (another type of female hormone) in your body.

Children and adolescents

Zafril is not indicated in girls before menarche (first menstruation).

Use of Zafril may affect the bone resistance of adolescents (12 to less than 18 years). Therefore, if you are under 18 years old, your doctor will carefully evaluate the benefits and risks of taking Zafril for you as a patient, taking into account any possible risk factors for bone loss (osteoporosis).

Concomitant use of Zafril with other medications

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

Also, inform any other doctor or dentist who prescribes another medication (or pharmacist) that you are taking Zafril.

Some medications may affect the levels of Zafril in the blood and make it less effective or cause adverse effects.

These include:

• epilepsy(for example, phenytoin, barbiturates, primidone, carbamazepine, oxcarbazepine, topiramate, felbamate);
• tuberculosis(for example, rifampicin);
• HIV and hepatitis C infections(so-called protease inhibitors and non-nucleoside reverse transcriptase inhibitors such as ritonavir, nevirapine, efavirenz);
• fungal infections(griseofulvin, ketoconazole).

• herbal preparations containingSt. John's Wort.

Consult your doctor or pharmacist before using any medication.

Concomitant use of Zafril with food and beverages

During treatment with Zafril, you should avoid drinking grapefruit juice, as it may increase the levels of the medication in the blood. This may increase the risk of adverse effects.

Laboratory tests

If you need a blood test, inform your doctor or laboratory staff that you are taking Zafril, as it may affect the results of some tests.

Pregnancy, lactation, and fertility

Do not take Zafril if you are pregnant or breastfeeding.

Driving and operating machinery

No effects on the ability to drive and operate machinery have been observed in Zafril users.

Zafril contains lactose

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

Follow exactly the administration instructions for this medication as indicated by your doctor. If in doubt, consult your doctor or pharmacist again.

The recommended dose for adults is 1 tablet per day.

The following statements apply to Zafril unless your doctor tells you otherwise. Follow these instructions, otherwise you will not benefit fully from Zafril treatment.

You can start Zafril treatment on any day of your natural cycle.

Adults: take one tablet each day, preferably at the same time, with a little liquid if necessary. Once you have finished a pack, the next one should be started without interruption. Continue taking the tablets on days of menstrual bleeding as well.

If you take more Zafril than you should

No serious adverse effects have been reported from taking too many Zafril tablets at once. However, if you are concerned, contact your doctor.

In case of overdose or accidental ingestion, consult your doctor or pharmacist or call the Toxicological Information Service, phone: 91 562 04 20, indicating the medication and the amount ingested.

If you forget to take Zafril or experience vomiting or diarrhea

Zafril will be less effective if you forget to take a tablet. If you forget one or more tablets, take a single tablet as soon as you remember, and then continue the next day, taking the tablet at the usual time.

If you experience vomiting within 3-4 hours after taking a Zafril tablet or have intense diarrhea, there is a risk that your body will not absorb the active ingredient of the tablet. This is a situation similar to when you forget to take a tablet. After experiencing vomiting or diarrhea within 3-4 hours after taking Zafril, you should take another tablet as soon as possible.

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

If you interrupt Zafril treatment

If you interrupt Zafril treatment, your original endometriosis symptoms may return.

If you have any other questions about the use of this medication, ask your doctor or pharmacist.

Like all medicines, this medicine can cause side effects, although not everyone will experience them. These side effects are more common during the first months after starting to take Zafril and usually disappear with continued use. You may also experience changes in your bleeding pattern, such as spotting, irregular bleeding, or complete cessation of menstruation.

Frequent(affect up to 1 in 10 people)

• weight gain;
• depressive mood, sleep disorders, nervousness, loss of interest in sex, or mood swings;
• headaches or migraines;
• nausea, abdominal pain, flatulence, abdominal swelling, or vomiting;
• acne or hair loss;
• back pain;
• breast tenderness, ovarian cysts, or hot flashes;
• uterine or vaginal bleeding, including spotting;
• weakness or irritability.

Less frequent(affect up to 1 in 100people)

• low red blood cell count (anemia);
• weight loss or increased appetite;
• anxiety, depression, or mood swings;
• autonomic nervous system imbalance (which controls unconscious bodily functions, for example, sweating) or attention disorders;
• dry eyes;
• tinnitus (ringing or buzzing in the ears);
• unspecified circulatory problems or infrequent palpitations;
• low blood pressure;
• difficulty breathing;
• diarrhea, constipation, abdominal discomfort, gastrointestinal inflammation, gingivitis;
• dry skin, excessive sweating, intense itching all over the body, excessive hair growth with a male pattern (hirsutism), brittle nails, dandruff, dermatitis, abnormal hair growth, light sensitivity, or skin pigmentation problems;
• bone pain, muscle spasms, pain, or heaviness in the arms and hands, or in the legs and feet;
• urinary tract infection;
• vaginal candidiasis, genital dryness, vaginal discharge, pelvic pain, atrophic vaginal inflammation with secretions (vulvovaginitis atrofica) or one or more breast lumps;
• swelling due to fluid retention.

Additional side effects in adolescents (12 to less than 18 years): bone density loss.

Reporting side effects

If you experience any type of side effect, consult your doctor or pharmacist, even if it is a side effect that does not appear in this prospectus.You can also report them directly through the National System for Pharmacovigilance of Medicines for Human Use:www.notificaraRAM.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.

Store in the original packaging to protect it from light.

This medication does not require any special storage temperature.

Do not use this medication after the expiration date that appears on the packaging and on the blister 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 medications you no longer need at the SIGRE collection point at the pharmacy. If in doubt, ask your pharmacist how to dispose of packaging and medications you no longer need. By doing so, you will help protect the environment.

Composition of Zafril

The active ingredient is dienogest. Each tablet contains 2 mg of dienogest.

The other components are lactose monohydrate, maize pregelatinized starch, microcrystalline cellulose, povidone K-25, crospovidone (type A), talc, and magnesium stearate.

Appearance of Zafril and contents of the packaging

Zafril 2 mg tablets are white or off-white, round, with flat faces and beveled edges, with “G 93” engraved on one face and “RG” on the other. The diameter of the tablets is 7 mm.

Zafril 2 mg tablets EFG are presented in packaging of 28, 84, and 168 tablets in a PVC//Al hard blister calendar of green color in cardboard boxes.

Only some sizes of packaging may be commercially marketed.

Holder of the marketing authorization andresponsible for manufacturing

Gedeon Richter Plc.

Gyömroi út 19-21

1103 Budapest

Hungary

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

Gedeon Richter Ibérica S.A.

Sabino Arana, 28 – 4º 2ª

08028 Barcelona, Spain

This medicine has been authorized in the EEA member states under the following denominations:

Last review date of this leaflet:April 2021

Further detailed information about this medicine is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS) (http://www.aemps.gob.es)