Diemono tablets 2 mg No. 28

Instructions for Diemono tablets 2 mg No. 28

Composition

active ingredient: dienogest;

1 tablet contains 2 mg of dienogest;

Excipients: lactose monohydrate, corn starch, maltodextrin, magnesium stearate, hypromellose 15 CP, titanium dioxide (E 171), macrogol 4000, sodium citrate.

Dosage form

Film-coated tablets.

Main physicochemical properties: Round white tablets, film-coated, without coating defects, embossed with "m" on one side.

Pharmacotherapeutic group

Hormones of the sex glands and drugs used in pathologies of the genital organs. Progestogens. Derivatives of pregnadiene. Dienogest. ATX code G03D B08.

Pharmacological properties

Pharmacodynamics

Dienogest is a nortestosterone derivative without androgenic and with some antiandrogenic activity, which is approximately one third of the activity of cyproterone acetate. Dienogest binds to progesterone receptors in the uterus with only 10% relative affinity. Despite its low affinity for progesterone receptors, dienogest has 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 effects of estradiol on both eutopic and ectopic endometrium. With continuous use, dienogest leads to the creation of a hypoestrogenic, hypergestagenic endocrine environment, which causes initial decidualization of endometrial tissue with subsequent atrophy of endometrioid foci.

Performance data

The superiority of dienogest 2 mg over placebo was demonstrated in a 3-month study in 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 2 mg, a statistically significant difference was observed compared to placebo (∆ = 12.3 mm; 95% CI: 6.4–18.1; p < 0.0001) and a clinically meaningful reduction in pain compared to baseline (mean reduction = 27.4 mm ± 22.9).

After 3 months of treatment, a reduction of pelvic pain associated with endometriosis by 50% or more was achieved in 37.3% of patients receiving dienogest 2 mg (placebo: 19.8%) without a corresponding increase in the dose of concomitant analgesic; a reduction of 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 2 mg (placebo: 7.3%).

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

The results of the placebo-controlled studies were confirmed by the results obtained in a six-month active-controlled study compared with a gonadotropin-releasing hormone agonist in 252 patients with endometriosis.

Three studies involving 252 patients treated with dienogest at a daily dose of 2 mg demonstrated a significant reduction in endometrioid lesions after 6 months of treatment.

In a small study (n = 8 per dose group), it was demonstrated that the use of dienogest at a daily dose of 1 mg per day ensured the absence of ovulation after 1 month of therapy. The contraceptive efficacy of dienogest at 2 mg has not been evaluated in larger studies.

Safety data

Endogenous estrogen levels are only moderately suppressed with dienogest 2 mg.

Long-term results of studies on bone mineral density (BMD) and fracture risk in patients receiving dienogest 2 mg are currently unavailable. BMD was assessed in 21 adult patients before and after 6 months of dienogest 2 mg, and no decrease in mean BMD was observed.

In the 29 patients treated with leuprorelin acetate (LA), the mean reduction was 4.04% ± 4.84 (∆ between groups = 4.29%, 95% CI: 1.93–6.66, p < 0.0003) over the same period.

No significant effects on standard laboratory parameters (including blood count, blood chemistry, liver enzymes, lipids and HbA1C) were observed during treatment with dienogest 2 mg for 15 months (n = 168).

Safety data for teenagers

The safety of dienogest 2 mg on BMD was investigated in a 12-month uncontrolled clinical study in 111 adolescent patients (12 to <18 years) with clinically suspected or confirmed endometriosis. The mean relative change in lumbar spine BMD (L2-L4) from baseline in the 103 patients with BMD measurements was -1.2%. Repeat measurements 6 months after the end of treatment in the subgroup of patients with decreased BMD showed an increase in BMD of -0.6%.

A long-term post-marketing active observational study was conducted to investigate the incidence of new onset or worsening of clinically significant depression and anemia. A total of 27,840 women with newly initiated hormonal therapy for endometriosis participated in the study and were followed for up to 7 years.

A total of 3023 women were initiated on dienogest 2 mg and 3371 patients were initiated on other approved drugs for the treatment of endometriosis. The overall adjusted hazard ratio for anemia compared with other approved drugs for the treatment of endometriosis was 1.1 (95% CI: 0.4-2.6). The adjusted hazard ratio for depression compared with other approved drugs for the treatment of endometriosis was 1.8 (95% CI: 0.3-9.4). A slightly increased risk of depression in patients taking dienogest compared with other approved drugs for the treatment of endometriosis cannot be excluded.

Pharmacokinetics

Absorption

When taken orally, dienogest is rapidly and almost completely absorbed. The maximum serum concentration of 47 ng/ml is reached within 1.5 hours after a single dose. Bioavailability is approximately 91%. The pharmacokinetics of dienogest are dose-dependent in the dose range of 1–8 mg.

Distribution

Dienogest is bound to serum albumin and does not bind to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG). Only 10% of the total serum concentration of dienogest is found as free steroid, and 90% is non-specifically bound to albumin.

The apparent volume of distribution of dienogest is 40 liters.

Biotransformation

Dienogest is completely metabolized by the known pathways of steroid metabolism, with the formation of mainly endocrinologically inactive metabolites. Based on in vitro and in vivo studies, CYP3A4 is the main enzyme involved in the metabolism of dienogest. The excretion of these metabolites occurs very rapidly, with dienogest remaining the main fraction in blood plasma in unchanged form.

The clearance rate from blood serum is 64 ml/min.

Breeding

The serum level of dienogest decreases in a biphasic manner. The terminal half-life is approximately 9–10 hours. Dienogest is excreted as metabolites in urine and feces in a ratio of approximately 3:1 after oral administration of 0.1 mg/kg. The urinary half-life of metabolites is 14 hours. After oral administration, approximately 86% of the administered dose is excreted within a six-day period, most of this amount being excreted within the first 24 hours, mainly in the urine.

State of dynamic equilibrium

The pharmacokinetics of dienogest are independent of the level of GSH. With daily administration, the concentration of the substance in the blood serum increases by 1.24 times, reaching an equilibrium state after 4 days of use. The pharmacokinetics of dienogest after repeated administration of dienogest 2 mg can be predicted based on data on the pharmacokinetics of a single dose.

Patients with renal insufficiency

No specific studies of dienogest 2 mg have been conducted in patients with renal impairment.

Patients with hepatic insufficiency

No specific studies of dienogest 2 mg in patients with hepatic impairment have been conducted.

Preclinical safety data.

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

Indication

Treatment of endometriosis.

Contraindication

Diemono® should not be used in the presence of any of the following conditions or diseases. This information is partly derived from the use of other progestogen-only products. If any of these conditions or diseases occur during use of Diemono®, the drug should be discontinued immediately:

Hypersensitivity to the active substance or to any of the excipients; active venous thromboembolism; current or history of arterial or cardiovascular disease (e.g. myocardial infarction, stroke, ischemic heart disease); diabetes mellitus with vascular damage; current or history of severe liver disease until liver function tests return to normal; current or history of liver tumors (benign or malignant); known or suspected malignant tumors dependent on sex hormones; vaginal bleeding of unknown etiology.

Interaction with other medicinal products and other types of interactions

Note: To identify possible interactions, you should consult the instructions for medical use of medicines taken simultaneously.

The metabolism of progestogens, including dienogest, is mainly mediated by the cytochrome P450 3A4 (CYP3A4) system, which is located in the intestinal mucosa and in the liver. Therefore, inducers or inhibitors of CYP3A4 may affect progestogen metabolism.

Increased clearance of sex hormones due to enzyme induction may reduce the therapeutic effect of Diemono® and lead to adverse reactions, for example, changes in the pattern of menstrual bleeding.

Reduced clearance of sex hormones due to enzyme inhibition may lead to increased exposure to dienogest, which may lead to the development of adverse reactions.

Substances that increase the clearance of sex hormones (reduced effectiveness due to enzyme induction) are, for example:

phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly oxcarbazepine, topiramate, felbamate, griseofulvin, and products containing St. John's wort (Hypericum perforatum).

Enzyme induction may occur after a few days of treatment. Maximum enzyme induction is usually observed after a few weeks. After discontinuation of treatment, enzyme induction may persist for up to four weeks.

The effect of the CYP 3A4 inducer rifampicin was studied in a study involving healthy postmenopausal women. Concomitant administration of rifampicin and estradiol valerate/dienogest tablets resulted in a significant decrease in the steady-state concentrations and systemic exposure of dienogest and estradiol. The systemic exposure of dienogest and estradiol at steady state, as measured by AUC(0-24 hours), was reduced by 83% and 44%, respectively.

Substances with different effects on the clearance of sex hormones.

When used concomitantly with sex hormones, a large number of combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations of HCV inhibitors, may increase or decrease progestin plasma levels. The cumulative effect of such 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 a strong CYP3A4 inhibitor, ketoconazole, resulted in a 2.9-fold increase in steady-state AUC(0-24 hours) of dienogest. Concomitant use with a moderate inhibitor, erythromycin, resulted in a 1.6-fold increase in steady-state AUC(0-24 hours).

Effect of Diemono® on other drugs

Based on the results of in vitro inhibition studies, clinically significant interactions of dienogest with other drugs metabolized by cytochrome P450 enzymes are unlikely.

Interaction with food products

A standardized high-fat meal did not affect the bioavailability of Diemono®.

Laboratory tests

The use of progestogens may affect the results of some laboratory tests, in particular biochemical parameters of the liver, thyroid gland, renal and adrenal function, levels of proteins (carriers) in the blood plasma (e.g. corticoid-binding globulin and lipid/lipoprotein fractions), parameters of carbohydrate metabolism and indicators of coagulation and fibrinolysis. Changes, as a rule, remain within the limits of the laboratory norm.

Application features

Reservation

Since Diemono® contains only a progestogen, it is considered that the special precautions and precautions for the use of progestogen-only preparations also apply to Diemono®.

In the presence or exacerbation of any of the conditions/risk factors listed below, an individual risk-benefit analysis should be performed before initiating or continuing therapy with Diemono®.

Heavy uterine bleeding

Uterine bleeding, for example in women with uterine adenomyosis or uterine leiomyoma, may be aggravated by the use of Diemono®. If the bleeding is severe and does not stop for a long time, it may lead to anemia (in some cases severe). In the event of anemia, discontinuation of Diemono® should be considered.

Change in bleeding pattern

In most patients, when taking dienogest 2 mg, the pattern of menstrual bleeding changes (see section "Adverse reactions").

Circulatory disorders

Some studies suggest a slight, but not statistically significant, increase in the risk of venous thromboembolism (deep vein thrombosis, pulmonary embolism) associated with the use of progestogen-only products. The following are generally recognized factors that increase the risk of venous thromboembolism (VTE): personal or family history (e.g., VTE in siblings or parents at a relatively young age), age, obesity, prolonged immobilization, major surgery or trauma. In the event of prolonged immobilization, it is recommended to discontinue the use of Diemono® (in the case of elective surgery at least 4 weeks before it) and not to resume it until 2 weeks after full recovery of mobility.

It is important to remember the increased risk of thromboembolism in the postpartum period.

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

Tumors

A meta-analysis of 54 epidemiological studies suggests a small increased relative risk (RR = 1.24) of breast cancer in women using oral contraceptives (OCs), mainly those containing estrogen-progestogen. 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 breast cancer diagnoses in women who use or have recently used COCs is small in relation to the overall risk of breast cancer. There is a similar risk of breast cancer in women who have used progestogen-only pills or COCs. However, the information on progestogen-only pills is based on a much smaller number of women using them and is therefore less conclusive than the data on COCs. The results of these studies do not provide evidence of a causal relationship. The increased risk may be due to earlier diagnosis of breast cancer in women who use OCs, or to the biological action of these drugs, or a combination of both factors. There is a tendency for breast cancer detected in women who have ever used OCs to be clinically less severe than in women who have never used oral contraceptives.

In isolated cases, benign and, even more rarely, malignant liver tumors have been observed in women taking hormonal agents similar to those contained in Diemono®. In some cases, such tumors have led to life-threatening intra-abdominal bleeding. In the event of complaints of severe pain in the epigastric region, liver enlargement, or signs of intra-abdominal bleeding, the possibility of liver tumors should be considered in the differential diagnosis in women taking Diemono®.

Osteoporosis

Changes in bone mineral density (BMD).

Dienogest 2 mg, in the treatment of adolescents (12 - < 18 years) for 12 months, was associated with a decrease in mean bone mineral density (BMD) at the lumbar spine (L2 - L4). The mean relative change in BMD at the end of treatment compared to baseline was 1.2% with a range between -6% and 5% (95% CI: -1.70% and -0.78%, n=103). Repeated measurements 6 months after the end of treatment in the subgroup with reduced BMD values showed a trend towards recovery (mean relative change from baseline: -2.3% at the end of treatment and -0.6% 6 months after the end of treatment with a range of -9% to 6% (95% CI: -1.20% to 0.06% [n=60]). The decrease in bone mineral density is of particular importance during adolescence and early puberty, a critical period of bone growth. It is not known whether the decrease in BMD in this population will lead to a decrease in peak bone mass and an increased risk of bone fracture in old age (see sections 4.2 and 4.3).

In patients at increased risk of osteoporosis, a careful benefit-risk assessment is necessary before initiating therapy with Diemono®, since endogenous estrogen levels are moderately reduced during therapy with this medicinal product (see section "Pharmacodynamics").

Adequate intake of calcium and vitamin D through diet or dietary supplements is important for bone health in women of all ages.

Other states

Patients with a history of depression should be carefully monitored and the drug should be discontinued if severe depression develops.

Dienogest generally does not affect blood pressure in normotensive women. In the event of prolonged clinically significant hypertension during the use of Diemono®, it is recommended to discontinue it and treat the hypertension.

Dienogest may have a minor effect on peripheral insulin resistance and glucose tolerance. Women with diabetes mellitus, particularly those with a history of gestational diabetes mellitus, should be carefully monitored during the use of Diemono®.

Chloasma may occasionally develop, especially in women with a history of chloasma during pregnancy. Women prone to chloasma should avoid exposure to direct sunlight or ultraviolet radiation while taking Diemono®.

The risk of ectopic pregnancy in women using progestogen-only contraceptives is higher than in women using combined oral contraceptives. Therefore, Diemono® should only be prescribed to women with a history of ectopic pregnancy or tubal dysfunction after a careful benefit-risk assessment.

During the use of Diemono®, persistent follicles (often called functional ovarian cysts) may occur. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain.

Diemono® contains lactose. 1 tablet contains 48.6 mg of lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Diemono®.

This medicinal product contains 23 mg of sodium citrate per tablet. Caution should be exercised when used in patients on a controlled sodium diet.

Ability to influence reaction speed when driving vehicles or other mechanisms

No effects on the ability to drive or use machines were observed in patients taking drugs containing dienogest.

Use during pregnancy or 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 5.2).

Diemono® should not be used in pregnant women, as there is no need to treat endometriosis during pregnancy.

Breast-feeding

The use of Diemono® during breastfeeding is not recommended.

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

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Diemono® therapy, taking into account the benefit of breast-feeding for the child and the need for therapy for the woman.

Fertility

Based on the available data, it can be stated that ovulation is suppressed in most patients during treatment with Diemono®. However, Diemono® is not a contraceptive.

If contraception is required, a non-hormonal method of contraception should be used in addition (see section “Method of administration and dosage”).

Based on available data, it can be stated that the menstrual cycle returns to normal within 2 months after discontinuation of Diemono® treatment.

Method of administration and doses

Method of application

Oral use.

Dosage regimen

Take 1 tablet daily without a break in taking the drug at about the same time, with a small amount of liquid. The tablets can be taken regardless of meals.

The tablets should be taken regularly, regardless of vaginal bleeding. As soon as the tablets from one package are finished, start taking the tablets from the next package without taking a break in taking the medicine.

There is no experience with the treatment of patients with endometriosis with Diemono® for longer than 15 months.

You can start taking the drug on any day of the menstrual cycle.

Any hormonal contraceptives should be discontinued prior to initiating therapy with Diemono®. If contraception is necessary, a non-hormonal method of contraception (e.g., barrier method) should be used in addition.

Skipping a medication

In case of missed tablets, vomiting and/or diarrhoea (which occurred during
3-4 hours after taking the tablet), the effectiveness of Diemono® may be reduced. If one or more tablets are missed, 1 tablet should be taken as soon as the woman remembers, and the next one should be taken at the usual time. Similarly, a tablet that has not been absorbed due to vomiting or diarrhea should be replaced with another tablet.

Elderly patients

There are no relevant indications for the use of Diemono® in the treatment of elderly patients.

Patients with hepatic insufficiency

The use of Diemono® in the treatment of patients with severe liver disease, present or in history, is contraindicated (see section "Contraindications").

Patients with renal insufficiency

There is no evidence that dose adjustment is necessary for patients with renal insufficiency.

Children

Taking Diemono® is not indicated for children and adolescents before the onset of menarche.

The safety and efficacy of dienogest 2 mg tablets were evaluated in an uncontrolled clinical study over 12 months, which included 111 adolescent patients (aged 12 - < 18 years) with clinical suspicion of endometriosis or a confirmed diagnosis of endometriosis (see sections 4.4 and 5.1).

Overdose

Acute toxicity studies of dienogest do not indicate a risk of acute adverse reactions in case of unintentional administration of several daily therapeutic doses. There is no specific antidote. The use of dienogest at a dose of 20–30 mg per day (which is 10–15 times the dose in Diemono®) for more than 24 weeks was very well tolerated.

Adverse reactions

Adverse reactions are described according to MedDRA. The most appropriate MedDRA term to describe a particular reaction and related conditions is used.

Adverse reactions most often develop during the first months after starting Diemono® and disappear with continued treatment. Changes in menstrual bleeding patterns, such as spotting, irregular bleeding or amenorrhea, may occur. The following adverse reactions have been reported in patients receiving dienogest 2 mg.

The most frequently reported adverse reactions during treatment with dienogest 2 mg are headache (9.0%), breast pain (5.4%), depressed mood (5.1%) and acne (5.1%).

In addition, most patients treated with dienogest 2 mg experienced a change in menstrual bleeding pattern. Menstrual bleeding patterns were assessed systematically using patient diaries and analyzed using the WHO method over a 90-day reporting period. During the first 90 days of treatment with dienogest 2 mg, 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 previous 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 menstrual bleeding, i.e. not falling into any of the previous categories (22.8%). Changes in menstrual bleeding patterns were only occasionally reported as adverse reactions in patients (see table of adverse reactions).

Table 1 lists the adverse reactions according to MedDRA classification (MedDRA SOCs) reported during treatment with dienogest 2 mg and their frequency. Within each grouping, adverse reactions are presented in order of decreasing frequency.

The frequency is based on pooled data from four clinical studies involving 332 patients (100%).

Table 1. Adverse reactions, phase III clinical studies, N= 332:

Decreased bone mineral density

In an uncontrolled clinical study involving 111 adolescent patients (12 to <18 years) treated with dienogest 2 mg, 103 patients had BMD measured. Approximately 72% of the study participants had a decrease in BMD at the lumbar spine (L2-L4) after 12 months of treatment (see section 4.4).

Reporting suspected adverse reactions is very important. Healthcare professionals and patients should report any suspected adverse reactions via the national reporting system.

Expiration date

3 years.

Storage conditions

No special storage conditions required. Keep out of the reach of children.

Packaging

28 tablets in a blister; 1 blister in a pack.

Vacation category

According to the recipe.

Producer

Mibe GmbH Arcnaymittel.

Location of the manufacturer and its business address

Münchenerstrasse 15, Brena, Saxony-Anhalt, 06796, Germany.