Mitren

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Miren (Mitren)

Composition:

Active substance: dienogest;

1 tablet contains 2 mg of dienogest;

Excipients: lactose monohydrate; corn starch; povidone K-30; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round, flat tablets.

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

Pharmacological Properties

Pharmacodynamics

Dienogest is a derivative of nortestosterone with no 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, thereby suppressing the trophic effects of estradiol on eutopic and ectopic endometrium. With continuous administration, dienogest creates a hypoestrogenic, hypergestagenic endocrine environment, leading to initial decidualization of endometrial tissue followed by atrophy of endometriotic lesions.

Efficacy data

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

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

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

Results from placebo-controlled trials were confirmed by those obtained in a six-month active-controlled study comparing dienogest with a gonadotropin-releasing hormone agonist, involving 252 patients with endometriosis.

Three studies involving 252 patients receiving dienogest at a dose of 2 mg per day 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 per day resulted in absence of ovulation after 1 month of therapy. The contraceptive efficacy of dienogest has not been studied in larger trials.

Safety data

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

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

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

The safety of dienogest with respect to 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 was -1.2%. Repeat 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, carcinogenic potential, and reproductive toxicity studies. However, it should be noted that sex steroids may promote the growth of certain hormone-dependent tissues and tumors.

Safety data from long-term use

An observational post-marketing study with active surveillance was conducted to determine the incidence of new-onset or worsening clinically significant depression and the occurrence of anemia. A total of 27,840 women who were newly prescribed hormonal therapy for the treatment of endometriosis were enrolled 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 ruled out.

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 exists 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 from plasma such that unchanged dienogest remains the predominant compound in plasma.

Serum clearance is 64 mL/min.

Elimination

Serum levels of dienogest decline in a biphasic manner, with an elimination 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 elimination half-life of metabolites in urine is approximately 14 hours. After oral administration, 86% of the administered dose is excreted within 6 days, with most of this amount eliminated within the first 24 hours, primarily via urine.

Steady state. The pharmacokinetics of dienogest are independent of SHBG levels. With daily administration, serum concentrations increase by a factor of 1.24, reaching steady state after 4 days of treatment. The pharmacokinetics of repeated doses of the medicinal product Miren can be predicted based on single-dose pharmacokinetic data.

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

Clinical characteristics.

Indications.

Treatment of endometriosis.

Contraindications.

The medicinal product Miren should not be used if any of the following conditions or diseases are present. These contraindications are 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 Miren, treatment should be discontinued immediately.

• Active venous thromboembolism.
• Arterial or cardiovascular diseases currently present or in medical history (e.g., myocardial infarction, cerebrovascular event, ischemic heart disease).
• Diabetes mellitus with vascular complications.
• Severe liver disease currently present or in medical history, until liver function tests return to normal.
• Liver tumors currently present or in medical 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, instructions for medical use of concomitantly administered medicinal products should be consulted.

Effect of other drugs on dienogest

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

Decreased clearance of sex hormones due to enzyme inhibition may reduce the therapeutic effect of Miren 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 within several weeks.

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

The effect of the CYP3A4 inducer rifampicin has been 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 dienogest and estradiol. The systemic exposure of dienogest and estradiol at steady state, 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 progestin. 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 enzyme 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 drugs whose metabolism is mediated by cytochrome P450 enzymes is unlikely.

Interaction with food

Consumption of food high in fat content did not affect the bioavailability of dienogest.

Laboratory tests

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

Special precautions for use.

Warnings.

Since Miren is a medicinal product containing only a progestogen, it is considered that special warnings and safety measures regarding the use of progestin-containing drugs also apply to this medicinal product, although not all warnings and precautions are based on relevant clinical study results specifically for this substance.

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

Severe uterine bleeding

Uterine bleeding, for example in women with adenomyosis or uterine leiomyoma, may increase during treatment with dienogest. If bleeding is severe and persistent over 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 dienogest affects the pattern of menstrual bleeding in most women (see section "Adverse reactions").

Circulatory disorders

According to some epidemiological data, there is an association between the use of progestogen-only medicinal products and an increased risk of myocardial infarction or cerebral thromboembolism. The risk of cardiovascular and cerebrovascular events is more likely related to age, arterial hypertension, and smoking. In women with arterial hypertension, the risk of stroke is slightly increased during treatment with progestogen-only drugs.

Some studies suggest a certain, although not statistically significant, increased risk of venous thromboembolism (deep vein thrombosis, pulmonary embolism) associated with the use of progestogen-only drugs. 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); advanced age; obesity; prolonged immobilization; major surgical procedures or trauma. In case of prolonged immobilization, treatment with Miren should be discontinued (in case of planned surgery – at least 4 weeks prior) and not restarted earlier than 2 weeks after full recovery.

The increased risk of thromboembolism in the postpartum period should also be taken into account.

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

Tumors

Data from a meta-analysis of 54 epidemiological studies indicate a slight increase in relative risk (RR = 1.24) of breast cancer among women using oral contraceptives (OCs), primarily combined estrogen-progestogen products. This increased risk gradually disappears within 10 years after discontinuation of combined oral contraceptives (COCs). 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 relative to the overall risk of breast cancer. The risk of detecting breast cancer is similar in women using progestogen-only drugs or COCs. However, data on progestogen-only drugs are derived from a much smaller number of users and are 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 the drugs, or a combination of both factors. A trend has been observed that breast cancer diagnosed in women who have ever used OCs tends to be less clinically advanced than in those who have never used OCs.

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

Osteoporosis. Changes in bone mineral density (BMD)

Use of dienogest in adolescents (12–18 years) over a 12-month treatment period was associated with a mean decrease in BMD at the lumbar spine (L2–L4) by 1.2%. 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: from -1.70 to -0.78, n = 103). Repeat measurements 6 months after treatment 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, range between -9% and 6% (95% CI: from -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 the reduction in BMD in this population may reduce peak bone mass and increase the risk of fractures in later life (see sections "Pharmacological properties" and "Children").

Before initiating treatment, the physician should carefully weigh the benefits of dienogest against potential risks for each individual adolescent, taking into account 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 adult women (see section "Pharmacological properties").

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

Other conditions

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

Dienogest usually does not affect blood pressure in normotensive women. However, if persistent, clinically significant arterial hypertension develops during treatment with Miren, the drug should be discontinued and hypertension treated accordingly.

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

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

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 dienogest treatment.

The risk of ectopic pregnancy is higher in women using progestogen-only contraceptives compared to women using COCs. Therefore, dienogest should be prescribed to women with a history of ectopic pregnancy or tubal dysfunction only after careful benefit-risk assessment.

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

Miren is not used in geriatric practice.

Lactose

One tablet of Miren contains 60.93 mg of lactose monohydrate. Patients with rare hereditary conditions of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption who are on a lactose-free diet should take into account the amount of this substance in Miren tablets.

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 reproductive toxicity (see section "Pharmacological properties").

Miren is not recommended for use during pregnancy, as there is no need to treat endometriosis during pregnancy.

Breastfeeding period

Treatment with dienogest during breastfeeding is not recommended. It is unknown whether dienogest passes into human breast milk. Animal studies indicate that dienogest is excreted in breast milk. A decision should be made whether to discontinue breastfeeding or to discontinue dienogest therapy, taking into account the benefit of breastfeeding for the child and the necessity of therapy for the mother.

Fertility

Based on available data, it can be stated that ovulation is inhibited in most patients during dienogest treatment. However, Miren is not a contraceptive.

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

Based on available data, it can be stated that the menstrual cycle returns to normal within 2 months after discontinuation of dienogest 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 medicinal products.

Method of Administration and Dosage

Method of Administration

For oral use.

Dosage

Take 1 tablet daily without interruption at approximately the same time each day, 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 any break in medication use.

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

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

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 Miren may be reduced. If one or more tablets are missed, the first tablet should be taken as soon as the woman remembers, and the next tablet should be taken at the usual time. Similarly, a tablet that was not absorbed due to vomiting or diarrhea should be replaced with another tablet.

Use in Special Patient Populations

Elderly Patients

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

Hepatic Impairment

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

Renal Impairment

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

Children

Miren is not indicated for use in children before menarche.

The safety and efficacy of dienogest were evaluated in an uncontrolled 12-month study involving 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 dienogest 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 dienogest in adolescents over a 12-month treatment period was associated with a mean decrease in bone mineral density (BMD) at the lumbar spine of 1.2%. After discontinuation of treatment, BMD increased again in these patients.

Changes in bone mineral density are of particular concern during adolescence and early stages of sexual maturation, which are critical periods for bone growth. It is unknown whether the reduction 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 and potential risks of dienogest use for each individual adolescent patient (see sections "Pharmacological Properties" and "Special Warnings and Precautions for Use").

Overdose

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

Adverse Reactions

Adverse reactions are listed according to MedDRA (Medical Dictionary for Regulatory Activities).

Adverse reactions most commonly occur during the first months of dienogest treatment and usually diminish over the course of therapy. Changes in bleeding patterns may occur, such as spotting, irregular bleeding, or amenorrhea.

The most frequently reported adverse events during dienogest treatment include headache (9.0%), breast discomfort (5.4%), depressed mood (5.1%), and acne (5.1%).

In addition, dienogest treatment 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, the following bleeding patterns were observed: 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: 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 reported during dienogest treatment and their frequency. Frequency is based on pooled data from four clinical trials involving 332 patients (100%). Within each category, adverse effects are listed in decreasing order of frequency.

Organ systems (MedDRA)	Common (from ≥ 1/100 to <1/10)	Uncommon (from ≥ 1/1000 to <1/100)
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, bloating, 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 spasms, limb pain, heaviness in limbs
Renal and urinary disorders		urinary tract infections
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, cystic fibrous breast disorders, breast induration
General disorders and administration site conditions	asthenic conditions, irritability	oedema

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

Other serious adverse reactions have been observed during the use of steroid sex hormones – progestogens (see section “Special instructions”): venous and arterial thromboembolic disorders, arterial hypertension, myocardial infarction, stroke, breast neoplasms, liver tumors, back discomfort, chloasma, cholestatic jaundice, osteoporosis, changes in glucose tolerance or effects on peripheral insulin resistance.

Decrease in bone mineral density

In an uncontrolled clinical study involving 111 adolescent patients (aged 12 to <18 years) receiving treatment with dienogest, 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 instructions”).

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach and sight of children.

Packaging.

28 tablets in a blister; 1 or 3 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LABORATORIOS LEON FARMA S.A./LABORATORIOS LEON FARMA S.A.

Manufacturer's address and place of business.

Poligono Industrial Navatejera, C/La Vallina s/n, Villaquilambre, 24193 Leon, Spain.