Visanne - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf Life and Storage

Active ingredients: DIenogest

Visanne 2 mg tablets

Why is Visanne used? What is it for?

Visanne is a preparation for the treatment of endometriosis (painful symptoms due to dislocation of the lining of the uterus). Visanne contains a hormone, the progestin dienogest

Contraindications When Visanne should not be used

Do not take Visanne if:

  • have a blood clot in the veins (thromboembolic disorder). This can occur, for example, in a blood vessel in the legs (deep vein thrombosis) or in the lungs (pulmonary embolism). See also "Visanne and venous thrombosis" below;
  • have or have ever had severe arterial disease, including cardiovascular disease such as heart attack or stroke or heart disease that causes reduced blood supply (angina pectoris). See "Visanne and arterial thrombosis" below;
  • have diabetes with vascular damage;
  • have or have ever had severe liver disease (and liver function values ​​have not normalized). Symptoms of liver disease can be yellowing of the skin and / or itching all over the body;
  • have or have ever had a benign or malignant liver tumor;
  • have or have ever had, or are suspected of having, a sex hormone-dependent malignancy, such as breast or genital organ cancer;
  • have unexplained vaginal bleeding;
  • you are allergic (hypersensitive) to dienogest or to any of the other ingredients of Visanne

If any of these conditions appear for the first time while using Visanne, stop treatment immediately and consult your doctor.

Precautions for use What you need to know before taking Visanne

Take special care with Visanne

You must not use hormonal contraceptives in any form (tablet, patch, intrauterine system) while taking Visanne.

Visanne is NOT a contraceptive. If you want to avoid pregnancy, you must use condoms or other non-hormonal contraceptive precautions.

In some situations you need to be especially careful while using Visanne and your doctor may need to see you regularly. Tell your doctor if any of the following apply to you:

self:

  • have ever had a blood clot (venous thromboembolism) or if one of your close family members had a blood clot at a relatively young age;
  • has a close relative who has had breast cancer;
  • have ever suffered from depression;
  • have high blood pressure or this condition occurs while using Visanne;
  • develop liver disease while using Visanne. Symptoms may include yellowing of the skin or eyes or itching all over the body. Also tell your doctor if these symptoms occurred during a previous pregnancy;
  • have diabetes or have had it during a previous pregnancy;
  • have ever had chloasma (brown patchy pigmentation on the skin, especially on the face). If so, avoid excessive exposure to the sun or ultraviolet rays;
  • suffer from pain in the lower abdomen while using Visanne.

During treatment with Visanne the chance of becoming pregnant is reduced as Visanne can have an effect on ovulation.

If you become pregnant while taking Visanne there is a slightly increased risk of ectopic pregnancy (the embryo develops outside the uterus). Tell your doctor before taking Visanne, if you have had an ectopic pregnancy in the past or if you have reduced function of the fallopian tubes.

Visanne and severe uterine bleeding

Uterine bleeding, for example in women with a disease characterized by the growth of the lining of the uterus (endometrium) within the muscular layer of the uterus, called internal endometriosis, or benign tumors of the uterus, also called uterine fibroids (uterine leiomyomas ), may worsen with the use of Visanne. If bleeding is heavy and continuous, this can lead to low red blood cell levels (anemia), which can in some cases be severe. In case of anemia, you should evaluate with your doctor whether to stop Visanne treatment.

Visanne and changes in the bleeding profile

Most women treated with Visanne experience changes in their menstrual bleeding profile (see section 4, "Possible side effects").

Visanne and venous blood clots

Some studies suggest that there may be a slight, but not statistically significant, increased risk of a blood clot in the legs (venous thromboembolism) associated with the use of progestogen-only preparations, such as Visanne. Very rarely blood clots they can cause severe permanent damage or can even be fatal.

The risk of having a venous blood clot increases:

  • with increasing age;
  • if you are overweight;
  • if you or any of your close relatives have had a blood clot in the leg (thrombosis), lung (pulmonary embolism), or other organs at a young age;
  • if you are due to have a surgery, a prolonged stay in bed or if you have had a serious accident. It is important that you tell your doctor in advance that you are taking Visanne, as treatment may need to be stopped. Your doctor will tell you when to restart Visanne. This will usually be possible about 2 weeks after you have regained complete mobility.

Visanne and arterial blood clots

There is little evidence of an association between the use of progestogen-only preparations, such as Visanne, and an increased risk of a blood clot, for example in the blood vessels of the heart (heart attack) or brain (stroke). In women hypertensive, the risk of stroke may be slightly increased by the use of progestogen-only preparations.

The risk of having an arterial blood clot increases:

  • if you smoke. It is strongly advised to stop smoking while using Visanne, especially if you are over 35 years old;
  • if you are overweight;
  • if one of your close relatives has had a heart attack or stroke at a young age;
  • if you have high blood pressure

Stop taking Visanne and consult your doctor immediately if you notice any possible signs of thrombosis, such as:

  • severe pain and / or swelling in one leg;
  • sudden severe pain in the chest, which may radiate to the left arm;
  • sudden lack of air;
  • sudden cough with no apparent cause;
  • unusual, intense or prolonged headache or worsening of migraine;
  • partial or complete loss of vision or double vision;
  • difficulty or inability to speak;
  • dizziness or fainting;
  • weakness, unusual sensations or numbness in any part of the body.

Visanne and cancer

From the data currently available, it is unclear whether Visanne increases the risk of breast cancer or not. Breast cancer has been observed slightly more frequently in women who use hormone preparations than in those who do not, but it is not known whether this is due to the treatment. For example, it is possible that, in women who use hormone preparations, more tumors are diagnosed, and earlier, because they undergo more frequent medical checks. The occurrence of breast cancer gradually decreases after stopping hormone treatment. It is important that you check your breasts regularly and contact your doctor if you feel any lump.

In women taking hormones, benign liver tumors and, even more rarely, malignant liver tumors have been observed in rare cases. Contact your doctor if you experience particularly severe abdominal pain.

Visanne and osteoporosis

If you have an increased risk of osteoporosis (brittle bones due to mineral loss), your doctor will carefully consider the risks and benefits of treatment with Visanne, because the medicine has a moderate suppressive effect on the production of estrogen (another type of female hormone ) by the body.

Interactions Which drugs or foods can change the effect of Visanne

Always tell your doctor about any medicines or herbal products you are taking. Also, tell any doctor or dentist who prescribes other medicines (or the pharmacist) that you are taking Visanne.

The following medicines may reduce the effect of Visanne:

medicines used to treat:

  • epilepsy (e.g. phenytoin, barbiturates, primidone, carbamazepine, oxcarbazepine, topiramate, felbamate);
  • tuberculosis (e.g. rifampicin);
  • HIV infections: non-nucleoside reverse transcriptase inhibitors (eg nevirapine);
  • other infections (antibiotics such as griseofulvin).
  • Preparations based on St. John's wort.

The following products may increase the levels of Visanne in the blood, resulting in side effects:

medicines such as:

  • anti-fungals (e.g. ketoconazole, itraconazole, fluconazole);
  • antibiotics (e.g. erythromycin, clarithromycin and roxithromycin);
  • antidepressants (e.g. nefazodone, fluvoxamine, fluoxetine);
  • antacids (e.g. cimetidine);
  • blood pressure medicines (e.g. diltiazem, verapamil);
  • protease inhibitors for HIV infections (eg ritonavir, saquinavir, indinavir, nelfinavir);
  • grapefruit juice.

Ask your doctor or pharmacist for advice before taking any medicine.

Taking Visanne with food and drink

You can take Visanne with or without food.

Warnings It is important to know that:

Laboratory analysis

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

Pregnancy and breastfeeding

Do not take Visanne if you are pregnant or breastfeeding.

Driving and using machines

No effects on ability to drive or use machines have been observed in users of Visanne.

Important information about some of the ingredients of Visanne

Visanne contains lactose. If you cannot tolerate certain sugars, contact your doctor before taking Visanne.

Dose, Method and Time of Administration How to use Visanne: Posology

Always take Visanne exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist. For adults, the usual dose is 1 tablet per day.

Unless otherwise prescribed by your doctor, please follow the instructions below, otherwise you may not benefit adequately from your treatment with Visanne.

You can start Visanne treatment on any day of your cycle.

Adults: take one tablet preferably at the same time each day, with the required amount of liquid. When one pack is finished, the next one must start without interruption. Continue to take the tablets even during the days of the menstrual cycle.

There is no experience in treating patients with endometriosis for periods longer than 15 months.

Overdose What to do if you have taken too much Visanne

There have been no reports of serious harmful effects of taking too many Visanne tablets at the same time. However, if you are concerned, contact your doctor.

If you forget to take Visanne or suffer from vomiting or diarrhea

The effectiveness of Visanne is reduced if you miss a tablet. If you forget to take one or more tablets, take only one tablet as soon as you remember and then continue taking the tablet at the usual time the next day.

If you vomit within 3-4 hours of taking Visanne, or if you have severe diarrhea, the active ingredient in the tablet may not be completely absorbed by your body. The situation is comparable to when you forget to take one tablet. After vomiting or diarrhea within 3-4 hours of taking Visanne, you should take another tablet as soon as possible.

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

If you stop taking Visanne

If you stop taking Visanne, your endometriosis symptoms may come back.

Side Effects What are the side effects of Visanne

Like all medicines, Visanne can cause side effects, although not everybody gets them. These effects most commonly occur during the first few months of treatment with Visanne and usually disappear with continued use. Changes in bleeding characteristics, such as spotting, irregular bleeding or cessation of periods, may also occur.

Common side effects (affecting 1 to 10 users in 100)

  • weight gain;
  • depressed mood, sleep disturbances, nervousness, loss of interest in sex, mood swings;
  • headache or migraine;
  • nausea, abdominal pain, bloating, abdominal bloating or vomiting;
  • acne or hair loss;
  • backache;
  • feeling of breast discomfort, ovarian cyst or hot flashes;
  • uterine / vaginal bleeding, including spotting;
  • weakness, irritability.

Uncommon side effects (affecting 1 to 10 users in 1,000)

  • anemia
  • weight loss or increased appetite;
  • anxiety, depression or mood swings;
  • imbalance of the autonomic nervous system (which controls unconscious bodily functions such as sweating) or attention disturbances;
  • dry eye;
  • tinnitus;
  • non-specific circulatory problems or uncommon palpitations;
  • low blood pressure;
  • breathlessness;
  • diarrhea, constipation, discomfort in the abdomen, inflammation of the stomach and intestines (gastrointestinal inflammation), inflammation of the gums (gingivitis);
  • dry skin, excessive sweating, intense itching all over the body, appearance of visible hair in typically male areas (hirsutism), brittle nails, dandruff, dermatitis, abnormal hair growth, hypersensitivity to light or skin pigmentation problems;
  • bone pain, muscle spasms, pain and / or feeling of heaviness in the arms, hands or legs and feet;
  • urinary tract infection;
  • vaginal thrush, vulvovaginal dryness, vaginal discharge, pelvic pain, atrophic inflammation of the genitals with discharge (atrophic vulvovaginitis) or breast lump (s);
  • swelling from water retention.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Expiry and Retention

Store in the original package to protect the medicine from light.

Keep out of the reach and sight of children.

Do not use Visanne after the expiry date which is stated on the pack after "EXP". The expiry date refers to the last day of the month.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

What Visanne contains

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

The other ingredients are: lactose monohydrate, potato starch, microcrystalline cellulose, povidone K 25, talc, crospovidone, magnesium stearate.

Description of what Visanne looks like and contents of the pack

Visanne tablets are white to off-white, round, flat and with beveled edges, 7 mm in diameter, with a "B" debossed on one side.

Visanne is available in blisters containing 14 film-coated tablets.

Boxes containing 28, 84 or 168 tablets are available.

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.

More information about Visanne can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, ADDITIONAL DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

VISANNE 2 MG TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 2 mg of dienogest.

Excipient: each tablet contains 62.8 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Tablet.

White to off-white, round, flat, bevelled edge tablets, 7 mm in diameter, with the letter "B" debossed on one side.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Treatment of endometriosis.

04.2 Posology and method of administration

Method of administration :

For oral use.

Dosage :

The dosage of Visanne is one tablet per day without interruption, to be taken preferably at the same time each day, if needed with a small amount of liquid. The tablet can be taken with or without meals.

The tablets should be taken continuously regardless of vaginal bleeding. When one pack is finished, the next one must be started without interruption.

There is no experience in the treatment of patients with endometriosis with Visanne for periods longer than 15 months.

Treatment can start on any day of the menstrual cycle.

Any contraceptive hormonal treatment must be stopped before starting Visanne. If contraceptive is needed, non-hormonal methods (e.g. barrier methods) should be employed.

Behavior in case of forgetting one or more tablets :

The effectiveness of Visanne may be reduced if one or more tablets are forgotten, vomiting and / or diarrhea (occurring within 3-4 hours of taking the tablet). If one or more tablets have been forgotten, the woman should take only one tablet as soon as she remembers and then continue taking the following day at the usual time. A tablet not absorbed due to vomiting or diarrhea should similarly be replaced with another tablet.

Additional information for particular categories of patients

Pediatric population :

The use of Visanne is not indicated in girls before menarche. The safety and efficacy of Visanne in adolescents (menarche to 18 years) has not yet been confirmed.

Geriatric population :

There are no indications regarding the use of Visanne in the geriatric population.

Patients with impaired hepatic function :

Visanne is contraindicated in patients with current or previous severe liver disease (see section 4.3).

Patients with impaired renal function :

There are no data to suggest the need for dose adjustment in patients with impaired renal function.

04.3 Contraindications

Visanne should not be used in any of the conditions listed below, which are derived in part from information on other progestogen-only preparations. Should any of these conditions arise during the use of Visanne, the treatment should be stopped immediately.

• active venous thromboembolic disease;

• existing or previous arterial and cardiovascular diseases (for example, myocardial infarction, cerebrovascular event, ischemic heart disease);

• diabetes mellitus with vascular involvement;

• current or previous severe liver disease, until the liver function indices return to normal;

• existing or previous liver tumors (benign or malignant);

• Known or suspected sex hormone dependent malignant tumors;

• vaginal bleeding of an unknown nature;

• hypersensitivity to the active substance or to any of the excipients.

04.4 Special warnings and appropriate precautions for use

Since Visanne is a progestogen-only preparation, it can be assumed that the special warnings and precautions for use for progestogen-only preparations are also valid for Visanne, although not all warnings and precautions are based on the findings. in clinical trials with Visanne.

If any of the conditions / risk factors listed below present or worsen, an individual benefit / risk analysis should be performed before starting or continuing treatment with Visanne.

Severe uterine bleeding

Uterine bleeding, for example in women with uterine adenomyosis or leiomyomas, may get worse with the use of Visanne. If bleeding is heavy and continuous, it can lead to anemia (severe in some cases). In case of anemia, it should be taken. in consideration of the interruption of Visanne.

Changes in the bleeding profile

The majority of patients treated with Visanne experience changes in their menstrual bleeding profile (see section 4.8).

Circulatory disorders

Based on epidemiological studies, progestogen-only preparations do not appear to be associated with an increased risk of myocardial infarction or cerebral thromboembolism. The risk of cardiovascular and cerebral events is rather correlated with increasing age, hypertension and smoking. In hypertensive women, the risk of stroke may be slightly increased by the use of progestogen-only preparations.

Some studies indicate that there may be a slightly increased risk, although not statistically significant, of venous thromboembolism (deep vein thrombosis, pulmonary embolism) in association with the use of progestogen-only preparations. The generally recognized risk factors for Venous thromboembolism (VTE) includes: positive personal or family history (VTE in a sibling or parent at a relatively early age), age, obesity, prolonged immobilization, major surgery or major trauma. , it is advisable to stop the use of Visanne (at least 4 weeks before in case of elective surgery) and not to resume treatment until 2 weeks after a complete recovery of mobility.

The increased risk of thromboembolism during the puerperium should be considered.

Treatment should be stopped immediately if symptoms of arterial or venous thrombosis occur or if such conditions are suspected.

Tumors

A meta-analysis of 54 epidemiological studies found that women using oral contraceptives (CO) have a slightly higher relative risk (RR = 1.24) of having breast cancer diagnosed, especially when using estrogen-progestagen preparations. The excess risk gradually disappears over the 10 years following discontinuation of combined oral contraceptives (COCs). Because breast cancer is rare in women under the age of 40, the extra number of breast cancers diagnosed in women who use or have recently used COCs is small in relation to the overall risk of breast cancer. The risk of having breast cancer diagnosed in users of progestogen-only preparations is comparable to that associated with the use of COCs. However, for progestogen-only preparations the data are based on a larger user population. limited and therefore less conclusive than those relating to COCs. These studies do not demonstrate the existence of a causal relationship. The observed increase in risk may be due to an earlier diagnosis of breast cancer in CO users, their biological effects, or a combination of both. Breast cancer diagnosed in CO users tends to be clinically less advanced compared to that diagnosed in women who have never used it.

Benign liver tumors and, even more rarely, malignant liver tumors have been reported rarely in women taking hormonal substances such as that contained in Visanne. In isolated cases, these tumors have resulted in life-threatening intra-abdominal haemorrhages. If a woman taking Visanne has severe upper abdominal pain, liver enlargement or signs of intra-abdominal bleeding, liver cancer should be considered in the differential diagnosis.

Osteoporosis

In patients at increased risk of osteoporosis a careful risk / benefit analysis should be performed before initiating treatment with Visanne, as endogenous estrogen levels are moderately decreased during treatment with Visanne (see section 5.1).

Other conditions

Patients with a history of depression should be closely monitored and treatment discontinued if depression recurs in severe form.

Generally, dienogest does not appear to affect blood pressure in normotensive women. However, if clinically significant hypertension develops during the use of Visanne and is maintained over time, it is advisable to stop taking Visanne and treat the hypertension.

The return of cholestatic jaundice and / or cholestatic pruritus first occurring in pregnancy or during previous sex steroid treatment requires discontinuation of Visanne.

Dienogest may have a mild effect on peripheral insulin resistance and glucose tolerance. Diabetic women, particularly those with a history of diabetes gravidarum, should be closely monitored while using Visanne.

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet rays while using Visanne.

Pregnancies occurring in users of progestogen-only preparations used as contraceptives are more likely to occur ectopic than pregnancies occurring in users of combined oral contraceptives. Therefore, in women with a history of ectopic pregnancy or tubal impairment, the use of Visanne should only be decided after a careful risk / benefit assessment.

Persistent ovarian follicles (often referred to as functional ovarian cysts) may occur during use of Visanne. Most of these follicles are asymptomatic, although sometimes they may be accompanied by pelvic pain.

Lactose

Each Visanne tablet contains 62.8 mg of lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption who are on a lactose-free diet, should take into account the amount contained in Visanne.

04.5 Interactions with other medicinal products and other forms of interaction

Effects of other medicines on Visanne

- Enzyme inhibitors or inducers (CYP3A4)

Progestogens including dienogest are mainly metabolised by the cytochrome P450 3A4 (CYP3A4) system located in the intestinal mucosa and in the liver. Therefore, inducers or inhibitors of CYP3A4 can influence the metabolism of the progestogen.

An increase in the clearance of sex hormones due to enzyme induction may reduce the therapeutic effect of Visanne with the possibility of undesirable effects such as changes in the uterine bleeding profile.

A reduction in the clearance of sex hormones due to enzyme inhibition may increase exposure to dienogest, with the possibility of undesirable effects.

- Substances with enzymatic induction activity

Drug interactions may occur (eg, phenytoin, barbiturates, primidone, carbamazepine, rifampicin and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, nevirapine, and products containing St. John's wort (Hypericum perforatum)) which induce microsomal enzymes (e.g. enzymes of the cytochrome P450 system) and which may lead to increased clearance of sex hormones.

Maximal enzyme induction is generally not observed for 2-3 weeks but may persist for at least 4 weeks after discontinuation of therapy.

The effect of the CYP3A4 inducer rifampicin was studied in healthy postmenopausal women. Co-administration of rifampicin with estradiol valerate / dienogest tablets led to a significant decrease in steady-state concentrations of dienogest and estradiol and systemic exposure to the active substances. Systemic exposure to dienogest and estradiol at steady state , as measured by AUC (0-24 hours), was reduced by 83% and 44%, respectively.

- Substances with enzymatic inhibiting activity

Known inhibitors of CYP3A4, such as azole antifungals (e.g. ketoconazole, itraconazole, fluconazole), cimetidine, verapamil, macrolides (e.g. erythromycin, clarithromycin and roxithromycin), diltiazem, saquinavir, indinavir, nelfinavir), antidepressants (e.g. nefazodone, fluvoxamine, fluoxetine) and grapefruit juice can increase plasma progestogens and cause undesirable effects.

A study to evaluate the effect of CYP3A4 inhibitors (ketoconazole, erythromycin) on the combination of estradiol valerate / dienogest showed that steady-state plasma levels of dienogest were increased. Co-administration with ketoconazole, a strong inhibitor, resulted in a 186% increase in steady-state dienogest AUC (0-24 hours). Concomitant administration with erythromycin, a moderate inhibitor, increased the steady-state AUC (0-24 hours) of dienogest by 62%.

The clinical relevance of these interactions is unknown.

Effects of dienogest on other medicinal products

Based on inhibition studies in vitro, a clinically relevant interaction of dienogest with the cytochrome P450 mediated metabolism of other medicinal products appears unlikely.

Note: Consult physician information on concomitant medications to identify potential interactions.

Interactions with food

A standard high-fat meal did not affect Visanne's bioavailability.

Laboratory tests

The use of progestogens may affect the results of some laboratory tests, including biochemical parameters relating to liver, thyroid, adrenal and renal function, plasma levels of (transporter) proteins such as, for example, corticosteroid-binding globulin and lipid / lipoprotein fractions, the parameters of glucose metabolism and the parameters of coagulation and fibrinolysis The variations generally remain within the laboratory reference values.

04.6 Pregnancy and breastfeeding

Pregnancy

There are limited data from the use of dienogest in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

Visanne should not be given to pregnant women because there is no need to treat endometriosis during pregnancy.

Feeding time

Treatment with Visanne while breastfeeding is not recommended.

It is not known whether dienogest is excreted in human milk. Animal data show that dienogest is excreted in rat milk.

A decision on whether to discontinue breast-feeding or to abstain from Visanne therapy must take into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

Based on the available data, ovulation is inhibited in the majority of patients during treatment with Visanne. However, Visanne is not a contraceptive.

If contraception is required, a non-hormonal method should be used (see section 4.2).

Based on the available data, the menstrual cycle returns to normal within two months of stopping treatment with Visanne.

04.7 Effects on ability to drive and use machines

Products containing dienogest do not affect the ability to drive or use machines.

04.8 Undesirable effects

Side effects occur most commonly during the first months of treatment with Visanne and tend to decrease with continued treatment. Changes in bleeding characteristics, such as spotting, irregular bleeding, or amenorrhea, may occur. The following side effects have been reported in users of Visanne.

The most frequently reported side effects during treatment with Visanne are: headache (9.0%), breast discomfort (5.4%), depressed mood (5.1%) and acne (5.1%).

In addition, changes in the menstrual bleeding profile occur in the majority of treated patients. Menstrual bleeding profiles were systematically assessed through patient diaries and analyzed using a 90 day reference period as recommended by the WHO (WHO 90 days reference period method). During the first 90 days of treatment with Visanne The following bleeding patterns were observed (n = 290; 100%): amenorrhea (1.7%), infrequent bleeding (27.2%), frequent bleeding (13.4%), irregular bleeding (35.2%) ), prolonged bleeding (38.3%), normal bleeding, i.e. none of the above categories (19.7%). During the fourth reference period, the following bleeding patterns were observed (n = 149; 100%): amenorrhea (28 , 2%), infrequent bleeding (24.2%), frequent bleeding (2.7%), irregular bleeding (21.5%), prolonged bleeding (4.0%), normal bleeding, i.e. none of the above categories ( 22.8%). Changes in menstrual bleeding profiles have been you only occasionally reported yourself as an adverse event by patients (see table of adverse events).

The frequencies of adverse drug reactions (ADRs) by MedDRA System Organ Class (MedDRA SOCs) reported with Visanne are summarized in the table below. Within each frequency class, undesirable effects are listed in order of decreasing frequency. Frequencies are defined as common (≥1 / 100,

Table 1. Undesirable Effects, Phase III Clinical Studies, N = 332


System and organ classification common Uncommon Disorders of the blood and lymphatic system anemia Metabolism and nutrition disorders weight gain weight decreased, increased appetite Psychiatric disorders depressed mood, sleep disturbance, nervousness, loss of libido, mood change anxiety, depression, mood swings Nervous system disorders headache, migraine autonomic nervous system imbalances, attention disturbance Eye disorders dry eye Ear and labyrinth disorders tinnitus Cardiac pathologies non-specific disturbance of the circulatory system, palpitations Vascular pathologies hypotension Respiratory, thoracic and mediastinal disorders dyspnea Gastrointestinal disorders nausea, abdominal pain, flatulence, abdominal distension, vomiting diarrhea, constipation, abdominal discomfort, gastrointestinal inflammation, gingivitis Skin and subcutaneous tissue disorders acne, alopecia dry skin, hyperhidrosis itching, hirsutism, onychoclasis, dandruff, dermatitis, abnormal hair growth, photosensitivity reaction, pigmentation disorders Musculoskeletal and connective tissue disorders backache bone pain, muscle spasms, pain in extremities, heaviness in extremities Renal and urinary disorders urinary tract infection Diseases of the reproductive system and breast breast discomfort, ovarian cyst, flushing, uterine / vaginal bleeding including spotting vaginal candidiasis, vulvovaginal dryness, genital discharge, pelvic pain, atrophic vulvovaginitis, breast lump, fibrocystic mastopathy, breast induration General disorders and administration site conditions asthenia, irritability edema

04.9 Overdose

Acute toxicity studies conducted with dienogest do not indicate a risk of acute adverse effects in case of inadvertent intake of a multiple of the daily therapeutic dose. There are no specific antidotes. The daily intake of 20-30 mg of dienogest (10-15 times the dose contained in Visanne) for a period of 24 weeks was very well tolerated.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: progestogens.

ATC code: G03D.

Dienogest is a derivative of nortestosterone devoid of androgenic activity, but rather endowed with an "antiandrogenic activity equal to about one third of that of cyproterone acetate. Dienogest binds to the progesterone receptor of the human uterus with a" relative affinity equal to only 10% of that of progesterone. Despite its low affinity for the progesterone receptor, dienogest has a potent progestin effect in vivo. Dienogest does not have significant androgenic, mineralocorticoid or glucocorticoid activity in vivo.

Dienogest acts on endometriosis by reducing the endogenous production of estradiol, with consequent suppression of the trophic effects of estradiol on both the eutopic and ectopic endometrium. Following continuous administration, dienogest creates a hypoestrogenic and hyperprogestinic endocrine environment, causing a initial decidualization of the endometrial tissue followed by atrophy of the endometriotic lesions.

Efficacy data

A 3-month study in 198 patients with endometriosis demonstrated the superiority of Visanne over placebo. Pelvic pain associated with endometriosis was measured on a Visual Analogue Scale (0-100 mm). After 3 months of treatment with Visanne a statistically significant difference was demonstrated compared to placebo (δ = 12.3 mm: 95% CI : 6.4-18.1; p

After three months of treatment, a reduction in pelvic pain associated with endometriosis of at least 50% with no relevant increase in concomitant pain relief was achieved in 37.3% of patients treated with Visanne (placebo: 19.8%); of pelvic pain associated with endometriosis of at least 75% without significant increase in concomitant pain relief was achieved in 18.6% of patients treated with Visanne (placebo: 7.3%).

The open-label extension of the same placebo-controlled study suggested continued improvement in pelvic pain associated with endometriosis for a treatment period of up to 15 months.

Results versus placebo are supported by those obtained in a 6-month GnRH agonist comparison study in 252 patients with endometriosis.

Three studies involving a total of 252 patients who received a 2 mg daily dose of dienogest demonstrated a significant reduction in endometriotic lesions after 6 months of treatment.

In a small study (n = 8 patients per dose), a daily dose of 1 mg dienogest was shown to induce anovulatory state after 1 month of treatment. The contraceptive efficacy of Visanne has not been evaluated in larger studies.

Safety data

Endogenous estrogen levels are moderately suppressed during treatment with Visanne.

There are currently no long-term data on bone mineral density (BMD) and fracture risk in users of Visanne. BMD was evaluated in 21 patients before and after six months of treatment with Visanne and no reduction in mean bone mineral density was observed. In 29 patients treated with leuprorelin acetate (LA), a mean reduction of 4.04% ± 4.84% was found after the same treatment period (δ between groups = 4.29%; 95% CI: 1.93 - 6.66; p

No significant changes in standard laboratory parameters (haematological and blood chemistry parameters, liver enzymes, lipidogram, and glycated hemoglobin (HbA1C) were observed during treatment with Visanne for up to 15 months (n = 168).

05.2 Pharmacokinetic properties

Absorption

After oral administration, dienogest is rapidly and almost completely absorbed. Peak serum concentrations of 47 ng / ml are reached approximately 1.5 hours after ingestion of a tablet. Bioavailability is approximately 91%. The pharmacokinetics of dienogest are dose proportional within the dose range of 1. -8 mg.

Distribution

Dienogest binds to serum albumin and not to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG). 10% of the total serum drug concentration is present as a free steroid, while 90% it is nonspecifically related to albumin.

The apparent volume of distribution (Vd / F) of dienogest is 40 l.

Metabolism

Dienogest is completely metabolised through the known pathways of steroid metabolism, with the formation of metabolites for the most part devoid of endocrine activity. Education in vitro and in vivo show that the main enzyme involved in the metabolism of dienogest is CYP3A4. The metabolites are excreted very rapidly and, consequently, the unchanged dienogest appears to be the predominant fraction in plasma.

The metabolic clearance from serum (Cl / F) is 64 ml / min.

Elimination

The serum levels of dienogest decrease with a biphasic trend. The terminal phase of elimination is characterized by a half-life of approximately 9-10 hours. Dienogest is excreted as metabolites with a urinary / faecal excretion ratio of approximately 3: 1 after oral administration of 0.1 mg / kg. The half-life of excretion of urinary metabolites is 14 hours. After oral administration, approximately 86% of the dose is eliminated within 6 days. Most of this amount is eliminated within the first 24 hours mainly in the urine.

Steady state conditions

The pharmacokinetics of dienogest are not affected by SHBG levels. Following daily intake, serum levels of the drug increase approximately 1.24-fold and steady state is reached after 4 days of treatment. The pharmacokinetics of dienogest after repeated administration of Visanne can be calculated from the single dose pharmacokinetics.

Pharmacokinetics in special patient populations

Visanne has not been specifically studied in subjects with impaired renal function.

Visanne has not been studied in subjects with impaired liver function.

05.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, carcinogenic potential and reproductive toxicity. However, it should be noted that sex steroids may promote the growth of certain tissues and hormone-dependent tumors.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Crospovidone;

lactose monohydrate;

magnesium stearate;

microcrystalline cellulose;

potato starch;

povidone K 25;

talc.

06.2 Incompatibility

Not relevant.

06.3 Period of validity

5 years

06.4 Special precautions for storage

Store in the original package to protect the medicine from light.

06.5 Nature of the immediate packaging and contents of the package

The tablets are packaged in blisters of clear green polyvinylidene chloride (PVDC) film, coated with polyvinyl chloride (PVC) and aluminum foil (heat-sealable opaque side).

Packs of:

28, 84 and 168 tablets.

Not all pack sizes may be marketed.

06.6 Instructions for use and handling

No special instructions

07.0 MARKETING AUTHORIZATION HOLDER

Bayer S.p.A. - Viale Certosa, 130 - 20156, Milan (MI)

08.0 MARKETING AUTHORIZATION NUMBER

AIC n. 041407014 / M - 28 tablets AIC n. 041407026 / M - 84 tablets

AIC n. 041407038 / M - 168 tablets

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

23/01/2013

10.0 DATE OF REVISION OF THE TEXT

01/2013

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

none:  sexual-health offal stomach-health