Dienogest zentiva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIENOGEST ZENTIVA (DIENOGEST ZENTIVA)

Composition:

Active substance: dienogest;

One film-coated tablet contains 2 mg of dienogest;

Excipients: lactose monohydrate; maize starch; povidone (K-30); sodium starch glycolate (type A); magnesium stearate;

Film coating: Aqua Polish White 014.17MS, containing hypromellose (E 464), hydroxypropylcellulose (E 463), talc (E 553b), hydrogenated cottonseed oil, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex, film-coated tablets, embossed with "2" 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 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 dienogest compared to placebo was demonstrated in a 3-month study involving 198 women with endometriosis. Pelvic pain associated with endometriosis was measured using a visual analog 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: 6.4–18.1; p<0.0001), along with a clinically meaningful reduction in pain from baseline (mean reduction = 27.4 mm ± 22.9).

After 3 months of treatment, a reduction of 50% or more in the frequency of pelvic pain episodes without an increase in analgesic dosage was observed in 37.3% of patients receiving dienogest (placebo: 19.8%). A reduction of 75% or more in pelvic pain episodes without increased analgesic use was observed in 18.6% of patients receiving dienogest (placebo: 7.3%).

Extension of this study showed continuous reduction in endometriosis-related pelvic pain with treatment up to 15 months.

Data from three studies in women receiving dienogest 2 mg daily indicate a significant reduction in endometriotic lesions after 6 months of treatment.

Results from placebo-controlled trials were confirmed by those from a 6-month active-controlled study comparing dienogest with a gonadotropin-releasing hormone (GnRH) agonist in 252 women with endometriosis.

In a small study, administration of dienogest at a dose of 1 mg daily resulted in absence of ovulation after 1 month of therapy. Dienogest has not been evaluated for contraceptive efficacy in larger studies.

Safety Data

During dienogest use, endogenous estrogen levels were moderately reduced.

To date, there are no long-term data on bone mineral density (BMD) and fracture risk in patients taking dienogest. BMD was assessed in 21 adult patients before treatment initiation and after 6 months of dienogest use, with no mean decrease observed. In 29 patients receiving leuprorelin acetate (LA), the mean decrease was 4.04% ± 4.84 over the same period (∆ between groups = 4.29%; 95% CI: 1.93–6.66; p<0.0003).

During dienogest use for up to 15 months (n=168), no significant changes were observed in standard laboratory parameters (hematological analysis, blood biochemistry, liver enzymes, lipids, and glycated hemoglobin).

Safety Data in Adolescents

The safety and efficacy of dienogest regarding BMD were evaluated in uncontrolled clinical studies over 12 months in 111 girls (12–18 years) with clinically confirmed endometriosis (see sections "Special Warnings" and "Pharmacological Properties"). The mean change in lumbar spine (L2–L4) BMD from baseline was 1.2% in 103 patients. In a subgroup of patients with reduced BMD, follow-up assessment 6 months after treatment completion showed an increase in BMD by 0.6%.

Nonclinical Safety Data

Nonclinical 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 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 anemia. A total of 27,840 women newly prescribed hormonal therapy for endometriosis were enrolled and followed for up to 7 years. Dienogest 2 mg was prescribed to 3,023 women, and 3,371 women received other endometriosis-approved medications. The overall adjusted risk ratio for new-onset anemia in women taking dienogest compared to those taking other endometriosis-approved medications was 1.1 (95% CI: 0.4, 2.6). The adjusted risk ratio for depression in women taking dienogest compared to those taking other endometriosis-approved medications was 1.8 (95% CI: 0.3, 9.4). A slight increase in the risk of depression in women taking dienogest compared to those taking other endometriosis-approved medications cannot be ruled out.

Pharmacokinetics

Absorption

Orally administered dienogest is rapidly and completely absorbed. Peak serum concentration, approximately 47 ng/mL, is reached about 1.5 hours after a single oral dose. Bioavailability is approximately 91%. The pharmacokinetics of dienogest are dose-proportional within the dose range of 1–8 mg.

Distribution

Dienogest binds to serum albumin and does not bind to sex hormone-binding globulin or corticosteroid-binding globulin. Ten percent of the total drug concentration in blood exists as free steroid, and 90% is non-specifically bound to albumin.

The theoretical volume of distribution (Vd/F) of dienogest is 40 L.

Biotransformation

Dienogest is metabolized via known steroid metabolic pathways, forming endocrinologically inactive metabolites. Based on in vitro inhibition studies and in vivo data, CYP3A4 is the primary enzyme involved in the metabolism of dienogest. Metabolites are eliminated very rapidly, so the majority of the drug concentration in plasma consists of unchanged dienogest.

The metabolic clearance rate in serum (Cl/F) is 64 mL/min.

Elimination

Serum dienogest concentration declines in two phases. The terminal elimination half-life is approximately 9–10 hours. Dienogest is excreted in the form of metabolites in urine and feces, with a urinary-to-fecal ratio of 3:1 after an oral dose of 0.1 mg/kg. The elimination half-life of metabolites is approximately 14 hours.

After oral administration, about 86% of the dose is excreted within 6 days, with a significant portion eliminated within 24 hours, predominantly in urine.

Steady State

The pharmacokinetics of dienogest are not influenced by sex hormone-binding globulin levels. With daily administration, serum drug concentration increases by a factor of 1.24 and reaches steady state by day 4 of treatment. The pharmacokinetics of dienogest upon repeated dosing can be predicted from single-dose pharmacokinetic data.

Pharmacokinetic Properties in Special Populations

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

Dienogest has not been studied for use in patients with hepatic insufficiency.

Clinical characteristics.

Indications.

Treatment of endometriosis.

Contraindications.

Dienogest Zentiva should not be used if any of the following conditions or diseases are present. This information is partly based on the use of other drugs containing only progestogens. If any of these conditions or diseases develops for the first time during treatment with Dienogest Zentiva, 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 drug.

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 drugs on dienogest

Progestogens, including dienogest, are mainly 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 Dienogest Zentiva and lead to undesirable effects, such as changes in the pattern of menstrual bleeding.

Decreased clearance of sex hormones due to enzyme inhibition may reduce the therapeutic effect of Dienogest Zentiva and 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 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 dienogest and estradiol. Systemic exposure to 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 various 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 inhibitor ketoconazole resulted in a 2.9-fold increase in AUC (0–24 hours) of dienogest at steady state. Concomitant administration with the moderate inhibitor erythromycin led to a 1.6-fold increase in AUC (0–24 hours) of dienogest at steady state.

Effect of dienogest on other medicinal products

Based on in vitro inhibition studies, clinically relevant interactions between dienogest and other drugs 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 Dienogest Zentiva.

Laboratory tests

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

Special precautions.

Warnings.

Since Dienogest Zentiva is a progestogen-only preparation, special precautions and safety measures applicable to progestin-containing preparations are considered to apply to Dienogest Zentiva as well, although not all warnings and precautions are based on appropriate clinical trial results specifically for this preparation.

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

Severe uterine bleeding

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

Changes in bleeding pattern

Treatment with Dienogest Zentiva 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, increased risk of venous thromboembolism (VTE) (deep vein thrombosis, pulmonary embolism) associated with the use of progestogen-only preparations. Well-established risk factors for 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, treatment with Dienogest Zentiva should be discontinued (for planned surgery – at least 4 weeks prior to the procedure) and not restarted until at least 2 weeks after full recovery.

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

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

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 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 additional number of 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 regarding progestogen-only preparations are based on a much smaller number of users and are therefore less conclusive than data for 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 medications, 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 Dienogest Zentiva, which in some instances 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 a liver tumor should be considered in the differential diagnosis of women taking Dienogest Zentiva.

Osteoporosis

Bone Mineral Density (BMD) changes.

Use of dienogest in adolescents (12–18 years) for a 12-month treatment period was associated with a mean decrease in BMD at the lumbar spine (L2–L4) of 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: –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% at 6 months post-treatment, range between –9% and 6%; 95% CI: –1.20% to 0.06%, n=60).

BMD changes are of particular concern during adolescence and early puberty, which are critical periods for bone growth. It is unknown whether reduced 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, physicians should weigh the benefits of using Dienogest Zentiva against potential risks for each individual adolescent, taking into account 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 has been observed in adult women (see section "Pharmacological properties").

In patients at increased risk of osteoporosis, a careful benefit-risk assessment should be performed before initiating treatment with Dienogest Zentiva, as endogenous estrogen levels are moderately reduced during treatment with Dienogest Zentiva (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 usually does not affect blood pressure in normotensive women. However, if persistent clinically evident arterial hypertension develops during treatment, Dienogest Zentiva should be discontinued and hypertension treated.

Treatment should be discontinued in case of recurrence of cholestatic jaundice and/or pruritus that occurred during pregnancy or previous use of sex hormones.

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 closely monitored during treatment with Dienogest Zentiva.

Melasma may occasionally develop, particularly in women with a history of melasma of pregnancy. Women prone to melasma should avoid direct sunlight or ultraviolet radiation during treatment with Dienogest Zentiva.

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

During treatment with Dienogest Zentiva, 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.

Not intended for use in geriatric practice.

Lactose

One tablet of Dienogest Zentiva contains 57.20 mg of lactose monohydrate. Patients with rare hereditary conditions associated with 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 one tablet of Dienogest Zentiva.

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").

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

Breastfeeding period

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

Fertility

Based on available data, ovulation is inhibited in most patients during treatment with Dienogest Zentiva. However, Dienogest Zentiva 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, the menstrual cycle returns to normal within 2 months after discontinuation of treatment with Dienogest Zentiva.

Ability to influence 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, approximately at the same time each day, swallowing with a small amount of liquid. The tablets may be taken regardless of food intake.

The tablets should be taken regularly, regardless of menstrual bleeding. As soon as the tablets from one pack are finished, treatment should continue with tablets from the next pack without any break in the use of the medicinal product.

There is no experience with treatment of endometriosis patients with Dienogest Zentiva 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 Dienogest Zentiva. If contraception is required, 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 efficacy of Dienogest Zentiva may be reduced. In case of missing one or more tablets, one 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 Dienogest Zentiva in this patient group.

Hepatic Impairment

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

Renal Impairment

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

Children

Dienogest Zentiva is contraindicated in children before the onset of first menstruation.

The safety and efficacy of dienogest have been studied in uncontrolled clinical trials over 12 months in 111 girls (aged 12–18 years) with clinically confirmed endometriosis (see sections "Pharmacological Properties", "Special Instructions for Use").

The use of Dienogest Zentiva in adolescents during the 12-month treatment period was associated with a 1.2% decrease in the mean lumbar spine BMD (bone mineral density). After discontinuation of treatment, BMD increased again in these patients.

Bone mineral density (BMD) is particularly important 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 of using Dienogest Zentiva against the potential risks for each individual adolescent (see sections "Pharmacological Properties", "Special Instructions for Use").

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 are available. Administration of 20–30 mg of dienogest per day (10–15 times higher than the dose in Dienogest Zentiva tablets) for more than 24 weeks was very well tolerated.

Adverse reactions

Adverse reactions are listed according to MedDRA.

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

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

In addition, treatment with dienogest 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 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).

Table 1 lists the adverse reactions reported during treatment with dienogest, classified according to MedDRA system organ classes (MedDRA SOCs), along with their frequencies.

Within each group, adverse effects 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 trials.

Table 1

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

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

Decrease in BMD

Administration of dienogest to adolescents (12–18 years of age) 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.

Reporting of adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

No special storage conditions required.

Keep out of reach and sight of children.

Packaging.

14 tablets in a blister. 2 or 6 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Haupt Pharma Muenster GmbH.

Manufacturer's address and location of operations.

Schleeweg 15, 48159 Muenster, North Rhine-Westphalia, Germany.