Vizan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VIZANNE® (VISANNE®)

Composition:

Active substance: dienogest;

1 tablet contains 2 mg of dienogest;

Excipients: lactose monohydrate, potato starch, microcrystalline cellulose, povidone K 25, talc, crospovidone, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white, round tablets, 7 mm in diameter, with bevelled edges, marked with the letter "V" on one side.

Pharmacotherapeutic group. Sex hormones and drugs used in pathologies of genital organs. Progestogens. ATC code G03DB08.

Pharmacological Properties.

Pharmacodynamics.

Dienogest is a derivative of nortestosterone without androgenic activity and with some antiandrogenic activity, approximately one-third that of cyproterone acetate. Dienogest binds to progesterone receptors in the uterus with only 10% relative affinity. Despite its low affinity for progesterone receptors, dienogest exerts a strong progestogenic effect in vivo. Dienogest does not exhibit significant androgenic, mineralocorticoid, or glucocorticoid activity in vivo.

Dienogest affects endometriosis by reducing endogenous estradiol production and thereby suppressing the trophic effect of estradiol on eutopic and ectopic endometrium. With continuous administration, dienogest creates a hypoestrogenic, hyperprogestogenic endocrine environment, leading to initial decidualization of endometrial tissue followed by atrophy of endometriotic lesions.

Efficacy data

The superiority of Visanne compared to placebo was demonstrated in a 3-month study involving 198 patients with endometriosis. Pelvic pain associated with endometriosis was measured using a visual analog scale (0–100 mm). After 3 months of treatment with Visanne, a statistically significant difference compared to placebo was observed (Δ = 12.3 mm; 95% CI: 6.4–18.1; p<0.0001), along with a clinically meaningful reduction in pain compared to baseline (mean reduction was 27.4 mm ± 22.9).

After 3 months of treatment, a reduction in pelvic pain associated with endometriosis by 50% or more was achieved in 37.3% of patients receiving Visanne (placebo: 19.8%), without a corresponding increase in the dose of concomitant analgesic; a reduction in pelvic pain by 75% or more (also without a corresponding increase in the dose of concomitant analgesic) was achieved in 18.6% of patients receiving Visanne (placebo: 7.3%).

An open-label extension of this placebo-controlled study showed continuous reduction in endometriosis-associated pelvic pain with treatment up to 15 months.

The results of placebo-controlled studies were confirmed by findings from a 6-month active-controlled study comparing dienogest to a gonadotropin-releasing hormone agonist, involving 252 patients with endometriosis.

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

In a small study (n=8 per dose group), administration of dienogest at a dose of 1 mg daily resulted in absence of ovulation after 1 month of therapy. Visanne has not been investigated for contraceptive efficacy in larger studies.

Safety data

Endogenous estrogen levels are only moderately suppressed during treatment with Visanne.

To date, long-term data on bone mineral density (BMD) and fracture risk in patients using Visanne are not available. BMD was evaluated in 21 adult patients before and after 6 months of treatment with Visanne. No mean decrease in BMD was observed. In 29 patients receiving leuprorelin acetate, a mean decrease of 4.04% ± 4.84 was observed over the same period (Δ between groups was 4.29%, 95% CI: 1.93–6.66, p<0.0003).

No significant effect on standard laboratory parameters, including blood count, blood biochemistry, liver enzyme levels, lipid levels, and HbA1c, was observed during 15 months of treatment with Visanne (N = 168).

Safety data in adolescents

The safety of Visanne regarding BMD was investigated in a 12-month uncontrolled study involving 111 adolescent patients (aged 12 to <18 years) with clinically suspected or confirmed endometriosis. The mean relative change in lumbar spine (L2–L4) BMD from baseline to end of treatment in 103 patients was -1.2%. Follow-up measurements 6 months after treatment completion in a subgroup with decreased BMD values showed an increase in BMD to -0.6%.

Non-clinical safety data

Non-clinical studies do not indicate a specific risk for humans based on standard repeated-dose toxicity, genotoxicity, carcinogenicity, and reproductive toxicity studies. However, it should be considered that sex steroids may promote the growth of certain hormone-dependent tissues and tumors.

Safety data with long-term use

An observational post-marketing study with active surveillance was conducted to determine the frequency of new onset or worsening of clinically significant depression and the occurrence of anemia. A total of 27,840 women newly prescribed hormonal therapy for the treatment of endometriosis were included and followed for up to 7 years. Dienogest 2 mg was prescribed to 3,023 women, and 3,371 patients were prescribed other medications approved for the treatment of endometriosis. The overall adjusted risk ratio for new cases of anemia in patients taking dienogest compared to those taking other approved endometriosis treatments was 1.1 (95% CI: 0.4–2.6). The adjusted risk ratio for depression in patients taking dienogest compared to those taking other approved endometriosis treatments was 1.8 (95% CI: 0.3–9.4). A slight increase in the risk of depression in patients taking dienogest compared to those taking other approved endometriosis treatments cannot be excluded.

Pharmacokinetics.

Absorption. After oral administration, dienogest is rapidly and completely absorbed. Maximum serum concentration is reached within 1.5 hours after a single oral dose and amounts to 47 ng/mL. The bioavailability of dienogest is approximately 91%. The pharmacokinetics of dienogest are dose-dependent within the dose range of 1–8 mg.

Distribution. Dienogest binds to serum albumin and does not bind to sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG). Only 10% of the total dienogest concentration in serum is present as free steroid, while 90% is non-specifically bound to albumin. The apparent volume of distribution of dienogest is 40 L.

Metabolism. Dienogest is completely metabolized via known steroid metabolic pathways, forming predominantly endocrinologically inactive metabolites. Based on in vitro and in vivo studies, CYP3A4 is the main enzyme involved in the metabolism of dienogest. These metabolites are rapidly eliminated in such a way that unchanged dienogest remains the predominant compound in plasma.

The serum clearance rate is 64 mL/min.

Elimination. The serum concentration of dienogest declines in a biphasic manner, with a half-life of 9–10 hours. Dienogest is excreted in the form of metabolites in urine and feces in a ratio of approximately 3:1 after an oral dose of 0.1 mg/kg. The half-life of metabolites in urine is approximately 14 hours. After oral administration, 86% of the administered dose is eliminated from the body within 6 days, with most of this amount excreted within the first 24 hours, primarily via urine.

Steady state. The pharmacokinetics of dienogest are independent of SHBG levels. With daily administration, the serum concentration increases by a factor of 1.24, reaching steady state after 4 days of use. The pharmacokinetics of dienogest after repeated administration of Visanne can be predicted based on single-dose pharmacokinetic data.

Pharmacokinetics in special patient populations. The pharmacokinetics of Visanne have not been studied in patients with renal impairment. The pharmacokinetics of Visanne have not been studied in patients with hepatic impairment.

Clinical characteristics.

Indications.

Treatment of endometriosis.

Contraindications.

Vizanne must not be used if any of the conditions or diseases listed below are present. This information is partially based on the use of other medicinal products containing only progestogens. If any of these conditions or diseases occurs for the first time during treatment with Vizanne, the medication should be discontinued immediately.

• Active venous thromboembolism.
• Arterial or cardiovascular diseases currently present or with history (e.g., myocardial infarction, cerebrovascular event, ischemic heart disease).
• Diabetes mellitus with vascular complications.
• Severe liver disease currently present or with history, until liver function tests return to normal.
• Liver tumors currently present or with history (benign or malignant).
• Known or suspected hormone-dependent malignant tumors.
• Vaginal bleeding of unknown etiology.
• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Note: To identify possible interactions, the package leaflets of concomitantly administered medicinal products should be consulted.

Effect of other medicinal products on Vizanne

Progestogens, including dienogest, are primarily metabolized by the cytochrome P450 3A4 (CYP3A4) system located in the intestinal mucosa and in the liver. Therefore, inducers or inhibitors of CYP3A4 may influence the metabolism of progestogens. Increased clearance of sex hormones due to enzyme induction may reduce the therapeutic effect of Vizanne and lead to adverse effects, such as changes in the pattern of menstrual bleeding.

Reduced clearance of sex hormones due to enzyme inhibition may also reduce the therapeutic effect of Vizanne and lead to the development of adverse reactions.

• Substances that increase the clearance of sex hormones (reduced efficacy through enzyme induction), e.g.: phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly oxcarbazepine, topiramate, felbamate, griseofulvin, and products containing St John’s wort (Hypericum perforatum).

Enzyme induction may be observed after several days of therapy. Maximum enzyme induction is generally reached after several weeks.

Enzyme induction may persist for up to 4 weeks after discontinuation of therapy.

The effect of the CYP3A4 inducer rifampicin was studied in healthy postmenopausal women. Concomitant administration of rifampicin with an oral formulation of estradiol valerate/dienogest resulted in a significant reduction in the steady-state concentration and systemic exposure of both dienogest and estradiol. The steady-state systemic exposure of dienogest and estradiol, measured as AUC (0–24 hours), decreased by 83% and 44%, respectively.

• Substances with variable effects on the clearance of sex hormones.

Concomitant use of sex hormones with a large number of combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors in combination with hepatitis C virus inhibitors may increase or decrease plasma levels of progestins. The overall effect of these changes may be clinically significant in some cases.

• Substances that reduce the clearance of sex hormones (enzyme inhibitors).

Dienogest is a substrate of cytochrome P450 (CYP) 3A4.

The clinical significance of potential interactions with enzyme inhibitors remains unknown.

Concomitant use of strong CYP3A4 inhibitors may increase plasma concentrations of dienogest.

Concomitant administration with the strong CYP3A4 inhibitor ketoconazole resulted in a 2.9-fold increase in the steady-state AUC (0–24 hours) of dienogest. Concomitant administration with the moderate inhibitor erythromycin resulted in a 1.6-fold increase in the steady-state AUC (0–24 hours) of dienogest.

Effect of dienogest on other medicinal products

Based on in vitro inhibition studies, a clinically significant interaction between dienogest and other medicinal products whose metabolism is mediated by cytochrome P450 enzymes is unlikely.

Interaction with food

Administration with a high-fat meal did not affect the bioavailability of Vizanne.

Laboratory tests

The use of progestogens may influence the results of certain laboratory tests, particularly liver, thyroid, kidney, and adrenal gland function tests, plasma levels of carrier proteins (e.g., SHBG) and lipid/lipoprotein fractions, carbohydrate metabolism parameters, and coagulation and fibrinolysis parameters. Changes are usually within normal laboratory reference ranges.

Special precautions.

Warnings.

Since Visanne is a preparation containing only a progestogen, it is considered that special warnings and safety measures regarding the use of progestin-containing drugs also apply to Visanne, although not all warnings and precautions are based on appropriate results of clinical trials specifically for this drug.

If any of the conditions/factors listed below worsen or occur for the first time, an individual risk/benefit assessment should be performed before initiating or continuing treatment with Visanne.

Severe uterine bleeding

Uterine bleeding, for example in women with adenomyosis or uterine leiomyoma, may increase during treatment with Visanne. If bleeding is severe and persists for a prolonged period, it may lead to anemia (in some cases severe). In such cases, discontinuation of the drug should be considered.

Changes in bleeding pattern

Treatment with Visanne affects the pattern of menstrual bleeding in most women (see section "Adverse reactions").

Circulatory disorders

Epidemiological studies provide limited data on a possible association between the use of progestogen-only preparations and an increased risk of myocardial infarction or cerebral thromboembolism. Cardiovascular and cerebrovascular events are more likely related to age, arterial hypertension, and smoking. In women with hypertension, the risk of stroke may slightly increase with the use of progestogen-only preparations.

Some studies suggest a certain, though not statistically significant, increased risk of venous thromboembolism (deep vein thrombosis, pulmonary artery embolism) associated with the use of progestogen-only preparations. Well-established risk factors for venous thromboembolism (VTE) include: personal or family history (e.g., VTE in siblings or parents at a relatively young age); age; obesity; prolonged immobilization; major surgical procedures or trauma. In case of prolonged immobilization, Visanne should be discontinued (at least 4 weeks before planned surgery) and should not be restarted until at least 2 weeks after full recovery.

Increased risk of thromboembolism in the postpartum period should be taken into account.

If symptoms of venous or arterial thrombotic disorders occur or are suspected, treatment should be discontinued.

Tumors

A meta-analysis of 54 epidemiological studies indicates a slight increase in relative risk (RR = 1.24) of breast cancer in women using oral contraceptives (OC), primarily those containing estrogen-progestogen. This increased risk gradually disappears within 10 years after discontinuation of combined oral contraceptives (COC). Since breast cancer is rare in women under 40 years of age, the increase in diagnosed cases among women currently or recently using COCs is small in relation to the overall risk of breast cancer. The risk of detecting breast cancer is similar in women who have used progestogen-only preparations or COCs. However, information on progestogen-only preparations is based on data from a much smaller number of users, and is therefore less conclusive than data on COCs. These study results do not provide evidence of a causal relationship. The increased risk may be due to earlier diagnosis of breast cancer in OC users, a biological effect of these drugs, or a combination of both factors. A trend has been observed that breast cancer diagnosed in women who have ever used OCs is clinically less advanced than in those who have never used oral contraceptives.

In rare cases, benign and even more rarely malignant liver tumors have been observed in women using hormonal substances similar to that contained in Visanne, which in some cases led to life-threatening intra-abdominal bleeding. If complaints of severe epigastric pain, hepatomegaly, or signs of intra-abdominal bleeding occur, the possibility of a liver tumor should be considered in the differential diagnosis in women taking Visanne.

Osteoporosis

Changes in bone mineral density (BMD).

Use of Visanne in adolescents (12–18 years) over a 12-month treatment period was associated with a 1.2% decrease in mean BMD at the lumbar spine (L2–L4). After discontinuation of treatment, BMD increased again in these patients.

The mean relative change in BMD from baseline to end of treatment was 1.2%, with a range between –6% and 5% (95% CI: –1.70% to –0.78%, n=103). Repeat measurements 6 months after treatment completion in a subgroup with reduced BMD values showed a trend toward recovery (mean relative change from baseline: –2.3% at end of treatment and –0.6% 6 months after treatment end, range between –9% and 6%; 95% CI: –1.20% to 0.06%, n=60).

Changes in bone mineral density are of particular importance during adolescence and early puberty, a critical period of bone growth. It is unknown whether reduced BMD in this population will reduce peak bone mass and increase the risk of fractures in later life (see sections "Pediatric use" and "Pharmacological properties").

Before initiating treatment, physicians should weigh the benefits of Visanne against potential risks for each individual adolescent, considering also the presence of significant risk factors for osteoporosis.

Adequate intake of calcium and vitamin D through diet or dietary supplements is important for maintaining healthy bone status in women of all age groups.

No decrease in BMD was observed in adults (see section "Pharmacodynamic properties").

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

Other conditions

Patients with a history of depression should be closely monitored, and treatment should be discontinued if severe depressive symptoms develop.

Dienogest generally does not affect blood pressure in normotensive women. However, if persistent clinically evident hypertension develops during treatment, Visanne should be discontinued and hypertension treated.

If cholestatic jaundice and/or pruritus, which occurred during pregnancy or previous use of sex hormones, recur, treatment should be discontinued.

Dienogest may have a minor effect on peripheral insulin resistance and glucose tolerance. Women with diabetes, especially those with a history of gestational diabetes, should be carefully monitored during treatment with Visanne.

Chloasma may occasionally develop, particularly in women with a history of chloasma of pregnancy. Women prone to chloasma should avoid direct sunlight or ultraviolet radiation during treatment with Visanne.

The likelihood of ectopic pregnancy in women using progestogen-only contraceptives is higher than in women using COCs. Therefore, for women with a history of ectopic pregnancy or impaired tubal function, the decision to use Visanne should be made only after careful risk/benefit assessment.

During treatment with Visanne, persistence of follicles (often referred to as functional ovarian cysts) may occur. Most of these follicles are asymptomatic, although some may be associated with pelvic pain.

Not used in geriatric practice.

Lactose

Each tablet of Visanne contains 62.8 mg of lactose monohydrate. Patients with rare hereditary conditions of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption, who are on a lactose-free diet, should consider the amount of this substance in the Visanne tablet.

Use during pregnancy or breastfeeding.

Pregnancy. Data on the use of dienogest in pregnant women are limited. Animal studies do not indicate direct or indirect risks of reproductive toxicity (see section "Pharmacological properties").

Visanne is not recommended for use in pregnant women, as there is no need to treat endometriosis during pregnancy.

Breastfeeding. Treatment with Visanne during breastfeeding is not recommended. It is unknown whether dienogest passes into human breast milk. Animal study data indicate that dienogest is excreted into breast milk. A decision should be made whether to discontinue breastfeeding or discontinue therapy with Visanne, taking into account the benefit of breastfeeding for the infant and the necessity of therapy for the woman.

Fertility. Based on available data, ovulation is inhibited in most patients during treatment with Visanne. However, Visanne is not a contraceptive.

If contraception is needed, a non-hormonal method of contraception should be used additionally (see section "Dosage and administration").

Based on available data, menstrual cycles return to normal within 2 months after discontinuation of Visanne treatment.

Ability to affect reaction speed when driving or operating machinery.

No effect on the ability to drive or operate machinery has been observed in patients taking dienogest-containing preparations.

Method of Administration and Dosage

Method of Administration

For oral use.

Dosage

Take 1 tablet daily without interruption in the use of the drug at approximately the same time each day, swallowing with a small amount of liquid. Tablets may be taken regardless of food intake.

Tablets should be taken regularly, regardless of menstrual bleeding. As soon as the tablets from one pack are finished, begin taking tablets from the next pack without making any break in the use of the medication.

Treatment may be initiated on any day of the menstrual cycle.

Any hormonal contraceptives should be discontinued before starting therapy with Visanne. If contraception is needed, an additional non-hormonal method of contraception (e.g., barrier method) should be used.

Missed Dose

If a tablet is missed, or if vomiting and/or diarrhea occur within 3–4 hours after taking the tablet, the effectiveness of Visanne may be reduced. If one or more tablets are missed, take 1 tablet as soon as remembered, and take the next tablet at the usual time. A tablet not absorbed due to vomiting or diarrhea should similarly be replaced with another tablet.

Additional Information on Use in Specific Patient Populations

Elderly Patients

There are no appropriate indications for the use of Visanne in this patient group.

Hepatic Impairment

The drug is contraindicated in patients with severe liver disease, either currently or in medical history (see section "Contraindications").

Renal Impairment

There are no data indicating the need for dose adjustment in patients with renal impairment.

Children

Visanne is not indicated for use in children before menarche.

The safety and efficacy of Visanne were evaluated in an uncontrolled 12-month study in 111 adolescent patients (12–<18 years) with clinically suspected or confirmed endometriosis (see sections "Special Warnings and Precautions for Use" and "Pharmacological Properties").

The efficacy of Visanne has been demonstrated in the treatment of endometriosis-associated pelvic pain in adolescents (12–18 years), with an overall favorable safety and tolerability profile.

Treatment with Visanne in adolescents for 12 months was associated with a mean decrease of 1.2% in bone mineral density (BMD) at the lumbar spine. After discontinuation of treatment, BMD increased again in these patients.

Changes in bone mineral density are of particular importance during adolescence and early puberty, which are critical periods of bone growth. It is unknown whether the decrease in BMD in this population may reduce peak bone mass and increase the risk of fractures in later life.

Therefore, physicians should carefully weigh the benefits of using Visanne against the potential risks for each individual adolescent patient (see sections "Special Warnings and Precautions for Use" and "Pharmacodynamic Properties").

Overdose

Acute toxicity studies conducted with dienogest did not indicate a risk of acute adverse reactions following accidental ingestion of several daily therapeutic doses. No specific antidotes exist. Doses of 20–30 mg dienogest per day (10–15 times higher than the dose in Visanne tablets) were well tolerated over periods exceeding 24 weeks.

Adverse reactions

Adverse reactions are listed according to MedDRA.

Adverse reactions most commonly occur during the first months of treatment with Vizanne and tend to resolve over time. Changes in bleeding patterns may occur, such as spotting, irregular bleeding, or amenorrhea.

The adverse reactions listed below have been reported during treatment with Vizanne. The most commonly reported adverse reactions during treatment with Vizanne include headache (9.0%), breast discomfort (5.4%), depressed mood (5.1%), and acne (5.1%).

In addition, treatment with Vizanne affects the nature of menstrual bleeding in most women. Menstrual bleeding patterns were systematically assessed using patient diaries and analyzed according to WHO criteria over a 90-day reporting period. During the first 90 days of treatment with Vizanne, 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%), and normal menstrual bleeding, i.e., not falling into any of the previous categories (19.7%). During the fourth reporting 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%), and normal menstrual bleeding, i.e., not falling into any of the previous categories (22.8%). Changes in menstrual bleeding patterns were only rarely reported as adverse reactions by patients (see table of adverse reactions).

The table below lists adverse reactions according to MedDRA System Organ Classes (MedDRA SOCs) reported during treatment with Vizanne and their frequency.

Within each group, adverse reactions are listed in order of decreasing frequency: common (≥ 1/100 to <1/10) and uncommon (≥ 1/1000 to <1/100). Frequency is based on pooled data from four clinical trials involving 332 patients (100%).

Adverse reactions, Phase III clinical trials, N=332

Organ system (MedDRA)	Common	Uncommon
Blood and lymphatic system disorders		anaemia
Metabolism and nutrition disorders	weight increased	weight decreased, increased appetite
Psychiatric disorders	depressed mood, sleep disorders, nervousness, decreased libido, mood changes	anxiety, depression, mood lability
Nervous system disorders	headache, migraine	autonomic dysfunction, attention disorders
Eye disorders		dry eyes
Ear and labyrinth disorders		tinnitus
Cardiac disorders		non-specific circulatory disorders, palpitations
Vascular disorders		arterial hypotension
Respiratory, thoracic and mediastinal disorders		dyspnoea
Gastrointestinal disorders	nausea, abdominal pain, flatulence, abdominal distension, vomiting	diarrhoea, constipation, abdominal discomfort, gastrointestinal inflammation, gingivitis
Skin and subcutaneous tissue disorders	acne, alopecia	dry skin, hyperhidrosis, pruritus, hirsutism, onycholysis, dandruff, dermatitis, hair growth disorders, photosensitivity reactions, pigmentation changes
Musculoskeletal and connective tissue disorders	back pain	bone pain, muscle cramps, limb pain, heaviness in limbs
Renal and urinary disorders		urinary tract infection
Reproductive system and breast disorders	breast discomfort, ovarian cyst, hot flushes, uterine/vaginal bleeding, including spotting	vaginal candidiasis, vulvar and vaginal dryness, genital discharge, pelvic pain, atrophic vaginitis, breast enlargement, fibrocystic breast disease, breast induration
General disorders and administration site conditions	asthenia, irritability	oedema

The following adverse reactions were also observed: follicular persistence, increased appetite, hypersensitivity reactions.

Other serious adverse reactions observed during the use of steroidal sex hormones and progestogens (see section "Special precautions for use"): venous and arterial thromboembolic events, arterial hypertension, myocardial infarction, stroke, breast neoplasms, liver tumors, back discomfort, chloasma, cholestatic jaundice, osteoporosis (see below), changes in glucose tolerance or effects on peripheral insulin resistance.

Decrease in bone mineral density

In an uncontrolled clinical study involving 111 adolescent female patients (aged 12 to <18 years) receiving Visanne treatment, bone mineral density (BMD) was measured in 103 patients. A decrease in lumbar spine (L2–L4) BMD was observed in approximately 72% of study participants after 12 months of treatment (see section "Special precautions for use").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is very important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions.

Shelf life.

5 years.

Storage conditions.

No special storage conditions required. Store in the original packaging, out of the reach of children.

Do not use the medicinal product after the expiry date stated on the packaging.

Packaging.

14 tablets in a blister; 2 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Bayer Weimar GmbH & Co. KG.

Manufacturer's address.

Droemerstraße 20, 99427 Weimar, Germany.