Endometrion

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ENDOMETRION (ENDOMETRION)

Composition:

Active substance: dienogest;

1 tablet contains 2 mg of dienogest;

Excipients: lactose monohydrate; microcrystalline cellulose; potato starch; crospovidone; povidone; talc; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: round, flat tablets with bevelled edges, white or almost white, with embossing “NC” on one side and “22” on the other.

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 and with some antiandrogenic activity, 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 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.

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, primarily forming 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.

The clearance rate from serum is 64 mL/min.

Elimination

Serum dienogest levels 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 from the body within 6 days, with the majority 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 within 4 days of treatment. The pharmacokinetics of dienogest after repeated dosing 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 impaired renal function.

The pharmacokinetics of dienogest have not been studied in patients with impaired hepatic function.

Clinical characteristics.

Indications.

Treatment of endometriosis.

Contraindications.

Endometrion should 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 progestogen. If any of these conditions or diseases occurs for the first time during treatment with Endometrion, 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.
• Liver tumors currently present or in medical history (benign or malignant).
• Known or suspected hormone-dependent malignant neoplasms.
• 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 instructions for medical use of concomitantly administered medicinal products should be consulted.

Effect of other medicinal products on Endometrion

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 Endometrion and lead to undesirable effects, such as changes in menstrual bleeding patterns.

Reduced clearance of sex hormones due to enzyme inhibition may reduce the therapeutic effect of Endometrion 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 within 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 a tablet 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 large numbers of combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, together with combinations of hepatitis C virus inhibitors, may increase or decrease plasma levels of progestin. The cumulative 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 use 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 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 Endometrion on other medicinal products

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

Interaction with food

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

Laboratory tests

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

Special precautions.

Warnings.

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

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

Severe uterine bleeding

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

Changes in bleeding pattern

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

Circulatory disorders

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

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 medicinal products. 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 surgery or trauma. In cases of prolonged immobilization, it is recommended to discontinue Endometrion (at least 4 weeks before elective surgery) and not to restart treatment 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.

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 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 products or COCs. However, data on progestogen-only products are based on a much smaller number of users and are therefore less conclusive than data on COCs. These studies 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 clinically less severe 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 Endometrion, 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 a liver tumor should be considered in the differential diagnosis of women taking Endometrion.

Osteoporosis

Changes in bone mineral density (BMD).

The use of 2 mg 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) of 1.2%. After discontinuation of treatment, BMD increased again in these patients.

The mean relative change in BMD from baseline to the 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 showed a trend toward recovery (mean relative change from baseline: –2.3% at end of treatment and –0.6% 6 months after treatment end, range between –9% and 6% (95% CI: –1.20% to 0.06%, n=60)).

Changes in bone mineral density are of particular importance during adolescence and early stages of sexual maturation, which are critical periods for bone growth. It is unknown whether the reduction in BMD in this population will reduce peak bone mass and increase the risk of fractures in later life (see sections "Paediatric population" and "Pharmacological properties").

Before initiating treatment, physicians should carefully weigh the benefits of using Endometrion 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 status in women of all age groups.

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

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

Other conditions

Depressed mood and depression are common adverse reactions during treatment with hormonal medications (see section "Adverse reactions"). Depression can be severe and is a known risk factor for suicidal behavior and suicide. Women should be informed to seek medical advice if they experience mood changes or symptoms of depression, including soon after starting treatment.

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

If cholestatic jaundice and/or pruritus, previously experienced during pregnancy or prior use of sex hormones, recurs, the medicinal product should be discontinued.

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, should be closely monitored during treatment with Endometrion.

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

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

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

Do not use in elderly patients.

Lactose

Each Endometrion tablet 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 the Endometrion tablet.

Use during pregnancy or breastfeeding.

Pregnancy

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

Endometrion is not recommended during pregnancy because there is no need to treat endometriosis during pregnancy.

Breastfeeding

Treatment with Endometrion 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 Endometrion, taking into account the benefits of breastfeeding for the child and the necessity of therapy for the mother.

Fertility

Based on available data, ovulation is inhibited in most patients during treatment with Endometrion. However, Endometrion 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 Endometrion treatment.

Effect on ability to drive and use machines.

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

Method of Administration and Dosage

Method of Administration

For oral use.

Dosage

Take 1 tablet daily without interruption in the use of the medicinal product, approximately at 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 any break in the use of the medicinal product.

There is no experience with treatment with Endometrion in patients with endometriosis for longer than 15 months.

The medicinal product may be started on any day of the menstrual cycle.

Any hormonal contraceptives should be discontinued prior to starting therapy with Endometrion. 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 Endometrion may be reduced. If one or more tablets are missed, 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 Groups

Elderly Patients

There are no appropriate indications for the use of Endometrion in patients of this age group.

Hepatic Impairment

The medicinal product 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

Endometrion is not indicated for use in children before menarche.

The safety and efficacy of 2 mg dienogest were evaluated in an uncontrolled study over 12 months in 111 adolescent patients (12 – <18 years) with clinically suspected or confirmed endometriosis (see sections "Special Warnings and Precautions for Use" and "Pharmacological Properties").

The efficacy of 2 mg 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 2 mg dienogest in adolescents over a 12-month treatment period was associated with a 1.2% decrease in mean bone mineral density (BMD) at the lumbar spine. After discontinuation of treatment, BMD increased again in these patients.

Disturbances in bone mineral density are of particular importance 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 Endometrion against the potential risks for each individual adolescent patient (see sections "Special Warnings and Precautions for Use" and "Pharmacodynamic Properties").

Overdose

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

Adverse reactions

Adverse reactions are listed according to MedDRA terminology.

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

The following adverse reactions have been reported during treatment with 2 mg of dienogest. The most commonly reported adverse events during treatment include headache (9.0%), breast discomfort (5.4%), depressed mood (5.1%), and acne (5.1%).

In addition, treatment with 2 mg dienogest affects the pattern 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 dienogest 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%), and normal menstrual bleeding, i.e., not falling into any of the previous categories (19.7%). During the fourth reporting period, the following bleeding patterns were observed (n=149; 100%): amenorrhea (28.2%), infrequent bleeding (24.2%), frequent bleeding (2.7%), irregular bleeding (21.5%), prolonged bleeding (4.0%), and normal menstrual bleeding, i.e., not falling into any of the previous categories (22.8%). Changes in menstrual bleeding patterns were only occasionally reported as adverse reactions by patients (see table of adverse reactions).

Table 1 lists the adverse reactions according to MedDRA System Organ Classes (MedDRA SOCs) reported during treatment with 2 mg dienogest, along with their frequency.

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 involving 332 patients (100%).

Table 1

Adverse reactions

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 and progestogens (see section "Special precautions for use"): venous and arterial thromboembolic disorders, arterial hypertension, myocardial infarction, stroke, breast neoplasms, liver tumors, back discomfort, chloasma, cholestatic jaundice, osteoporosis (see below), changes in glucose tolerance or effects on peripheral insulin resistance.

Decrease in bone mineral density

In an uncontrolled clinical study involving 111 adolescent patients (aged 12 to <18 years) receiving 2 mg of dienogest, 103 had measurements of BMD. A decrease in lumbar spine (L2–L4) BMD was observed in approximately 72% of study participants after 12 months of treatment (see section "Special precautions for use").

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions during the post-marketing period is very important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions.

Shelf life.

2 years.

Storage conditions.

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

Packaging.

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

Prescription category.

Prescription only.

Manufacturer.

Naari Pharma Private Limited.

Manufacturer's address and place of business.

Plot No. 14-16 & 55-57, Sector-5, IIE, Pantnagar, Rudrapur, Dist. Udham Singh Nagar, Uttarakhand, 263153, India.

Marketing Authorization Holder.

Naari B.V.

Address of the Marketing Authorization Holder.

Ritveldeven 102, 5222 AS 's-Hertogenbosch, The Netherlands.