Dimetrio

INSTRUCTIONS for medical use of the medicinal product Dimetrio (Dimetrio)

Composition:

Active ingredient: dienogest;

1 film-coated tablet contains 2 mg of dienogest;

Excipients: lactose monohydrate, corn starch, povidone (K-30), sodium starch glycolate (type A), magnesium stearate, purified water;

Film coating: hypromellose (E 464), hydroxypropyl cellulose (E 463), talc (E 553b), hydrogenated cottonseed oil, titanium dioxide (E 171), purified water.

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: white, round, biconvex tablets with "2" engraved on one side.

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 both 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 the medicinal product Dienogest 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 analogue scale (0–100 mm). After 3 months of treatment with Dienogest, a statistically significant difference compared to placebo was observed (Δ = 12.3 mm; 95% CI: 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 reduction in pelvic pain associated with endometriosis by 50% or more was achieved in 37.3% of patients receiving Dienogest (placebo: 19.8%), without a corresponding increase in the dose of concomitant analgesic; a reduction in pelvic pain associated with endometriosis by 75% or more (also without a corresponding increase in the dose of concomitant analgesic) was achieved in 18.6% of patients receiving Dienogest (placebo: 7.3%).

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

Results from 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 dosage group), administration of dienogest at a dose of 1 mg daily resulted in absence of ovulation after 1 month of therapy. The medicinal product Dienogest has not been studied for contraceptive efficacy in larger trials.

Safety data

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

Currently, long-term data on bone mineral density (BMD) and fracture risk in patients using Dienogest are not available. BMD was assessed in 21 adult patients before and after 6 months of treatment with Dienogest. No mean decrease in BMD was observed. In 29 patients receiving leuprorelin acetate, a mean decrease of 4.04% ± 4.84 was recorded over the same period (Δ between groups = 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).

Safety data in adolescents

The safety of Dienogest regarding BMD was evaluated in an uncontrolled 12-month 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%. Repeat measurement 6 months after treatment completion in a subgroup with reduced BMD values showed an increase in BMD to –0.6%.

Non-clinical safety data

Non-clinical study data 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 considered 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 anemia. A total of 27,840 women who were newly prescribed hormonal therapy for endometriosis treatment were enrolled and followed for up to 7 years. Dienogest 2 mg was prescribed to 3,023 women, and 3,371 patients received other medicinal products approved for endometriosis treatment. The overall adjusted hazard ratio for new-onset anemia in patients taking dienogest compared to those taking other approved endometriosis treatments was 1.1 (95% CI: 0.4–2.6). The adjusted hazard 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 primary enzyme involved in dienogest metabolism. These metabolites are rapidly eliminated from plasma such that unchanged dienogest is the predominant compound in plasma.

The serum clearance rate is 64 mL/min.

Elimination

Serum levels of dienogest decline 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 within 6 days, with the majority excreted 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 dienogest after repeated administration of Dienogest 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

Dimerio must not be used if any of the following conditions or diseases are present. This information is partly based on the use of other medicinal products containing only progestogens. If any of these conditions or diseases newly occur during treatment with Dimerio, the drug 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.
• Hepatic tumors currently present or in medical history (benign or malignant).
• Known or suspected hormonally-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 potential interactions, the package leaflets of concomitantly administered medicinal products should be consulted.

Effect of other medicinal products on Dimerio

Progestogens, including dienogest, are mainly 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 Dimerio and may lead to adverse reactions, such as changes in menstrual bleeding patterns.

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

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

Enzyme induction may occur after several days of therapy. Maximum enzyme induction is generally observed after 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 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 various combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, in combination with hepatitis C virus inhibitor combinations, may increase or decrease plasma levels of progestin. The combined 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 the plasma concentration of dienogest.

Concomitant use with the strong CYP3A4 inhibitor ketoconazole resulted in a 2.9-fold increase in the steady-state AUC (0–24 hours) of dienogest. Concomitant use 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, clinically significant interactions between dienogest and other medicinal products whose metabolism is mediated by cytochrome P450 enzymes are unlikely.

Interaction with food

Consumption of a high-fat meal did not affect the bioavailability of Dimerio.

Laboratory tests

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

Special precautions for use

Warnings

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

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

Severe uterine bleeding

Uterine bleeding, for example in women with adenomyosis or uterine leiomyoma, may increase during treatment with Dimetro. If bleeding is severe and persistent, 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 Dimetro 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 arterial hypertension, the risk of stroke may slightly increase with the use of progestogen-only preparations.

Some studies suggest a certain, although not statistically significant, increase in the risk of venous thromboembolism (deep vein thrombosis, pulmonary 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 cases of prolonged immobilization, Dimetro should be discontinued (at least 4 weeks before elective surgery) and not restarted until at least 2 weeks after full recovery.

An increased risk of thromboembolism should be considered during the postpartum period.

If symptoms of venous or arterial thrombotic disease 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 (OCs), primarily combined estrogen-progestogen contraceptives. This increased risk gradually disappears within 10 years after stopping 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 preparations or COCs. However, data on progestogen-only preparations are based on 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 these 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 oral contraceptives.

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 Dimetro, which in some cases led to life-threatening intra-abdominal bleeding. In case of complaints of severe epigastric pain, liver enlargement, or signs of intra-abdominal bleeding, the possibility of liver tumor should be considered in the differential diagnosis of women taking Dimetro.

Osteoporosis

Changes in bone mineral density (BMD).

Use of Dimetro 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% and –0.78%, n = 103). Repeat measurements 6 months after treatment cessation in a subgroup with reduced BMD showed a trend toward recovery (mean relative change from baseline: –2.3% at end of treatment and –0.6% 6 months after treatment cessation, range between –9% and 6% (95% CI: –1.20% and 0.06%, n = 60).

Changes in BMD are particularly significant during adolescence and early sexual maturation, 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 "Pharmacological properties" and "Children").

Before initiating treatment, the physician should weigh the benefits of using Dimetro 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 tissue in women of all age groups.

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

In patients at increased risk of osteoporosis, a careful risk-benefit assessment should be performed before initiating treatment with Dimetro, as endogenous estrogen levels are moderately reduced during treatment with Dimetro (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.

Depressed mood and depression are well-known adverse reactions that may occur during use of hormonal contraceptives (see section "Adverse reactions"). Depression can be a serious condition and is a well-known risk factor for suicidal behavior and suicide. Women should be advised to consult a physician if mood changes or symptoms of depression occur, including soon after starting treatment.

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

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 closely monitored during treatment with Dimetro.

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 Dimetro.

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

During treatment with Dimetro, follicular persistence (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 Dimetro 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 take into account the amount of this substance in Dimetro tablets.

Use during pregnancy or breastfeeding

Pregnancy

Limited data are available on the use of dienogest in pregnant women. Animal studies do not indicate a direct or indirect risk of reproductive toxicity (see section "Pharmacological properties").

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

Breastfeeding

Treatment with Dimetro 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 therapy with Dimetro, taking into account the benefit of breastfeeding for the infant and the necessity of therapy for the mother.

Fertility

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

If contraception is needed, a non-hormonal method of contraception should be used additionally (see section "Instructions for use and dosage").

Based on available data, the menstrual cycle returns to normal within 2 months after discontinuation of Dimetro 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 treatment 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, the next pack should be started immediately without a break in medication use.

There is no experience with treatment of patients with endometriosis using Dimetro for longer than 15 months.

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

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

Missed Dose

In case of missed tablet intake, vomiting, and/or diarrhea (occurring within 3–4 hours after tablet intake), the efficacy of Dimetro may be reduced. If one or more tablets are missed, 1 tablet should be taken as soon as the patient 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.

Additional Information on Use in Special Patient Populations

Elderly Patients

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

Hepatic Impairment

Dimetro 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

Dimetro is not indicated for use in children before menarche.

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

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

Treatment with Dimetro in adolescents over a 12-month period was associated with a 1.2% decrease in mean lumbar spine BMD. After discontinuation of treatment, BMD increased again in these patients.

BMD changes are of particular importance during adolescence and early stages of sexual maturation, which are critical periods for bone growth. It is unknown whether reduced BMD in this population may decrease peak bone mass and increase the risk of fractures in later life.

Therefore, physicians should carefully weigh the benefits of Dimetro treatment against the potential risks for each individual adolescent (see sections "Pharmacological Properties" and "Special Instructions").

Overdose

Acute toxicity studies conducted with dienogest did not indicate a risk of acute adverse reactions following accidental ingestion of multiple daily therapeutic doses. No specific antidotes are available. Administration of 20–30 mg dienogest per day (10–15 times higher than the dose in Dimetro tablets) for more than 24 weeks was very well tolerated.

Adverse reactions

Adverse reactions are described according to MedDRA.

Adverse reactions most commonly occur during the first months of treatment with Dimetréo and usually resolve during continued therapy. Changes in bleeding patterns may be observed, such as spotting, irregular bleeding, or amenorrhea.

Adverse reactions have been reported during treatment with Dimetréo. The most frequently reported adverse reactions during treatment with Dimetréo include headache (9.0%), breast discomfort (5.4%), depressed mood (5.1%), and acne (5.1%).

In addition, treatment with Dimetréo affects the pattern of menstrual bleeding in most women. Menstrual bleeding patterns were systematically assessed using patient diaries and analyzed according to the WHO method over a 90-day reporting period. During the first 90 days of Dimetréo therapy, 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 menstrual bleeding (i.e., none of the above 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%), normal menstrual bleeding (i.e., none of the above categories) (22.8%). Changes in menstrual bleeding patterns were only occasionally 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 Dimetréo and their frequency.

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

Adverse reactions, Phase III clinical trials, N = 332

(MedDRA)	Common	Uncommon
Blood and lymphatic system disorders		anaemia
Metabolism and nutrition disorders	weight increased	weight decreased, appetite increased
Psychiatric disorders	depressed mood, sleep disorders, nervousness, decreased libido, mood changes	anxiety, depression, mood lability
Nervous system disorders	headache, migraine	autonomic disturbance, attention disorders
Eye disorders		dry eye
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 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, vulvovaginal dryness, genital discharge, pelvic pain, atrophic vaginitis, breast enlargement, fibrocystic breast disease, breast tenderness
General disorders and administration site conditions	asthenic conditions, 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 – progestogens (see section "Dosage and Administration"): 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.

Decreased bone mineral density

In an uncontrolled clinical study involving 111 adolescent patients (aged 12 to <18 years) receiving treatment with Dimethrio, 103 had bone mineral density measurements. Approximately 72% of study participants experienced a decrease in lumbar spine (L2–L4) bone mineral density after 12 months of treatment (see section "Dosage and Administration").

Reporting suspected adverse reactions

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

Shelf life. 2 years.

Storage conditions. No special storage requirements for the medicinal product.

Packaging. 14 tablets per blister pack, 2 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer: Adamed Pharma S.A., Poland.

Manufacturer's address and location of its business activity:

ul. marsz. J. Pilsudskiego 5, 95–200, Pabianice, Poland.