Normetrilla (Tablets) Instructions for Use

Marketing Authorization Holder

Binnopharm Group LLC (Russia)

Manufactured By

Laboratorios Leon Farma, S.A. (Spain)

Contact Information

BINNOPHARM GROUP LLC (Russia)

ATC Code

G03DB08 (Dienogest)

Active Substance

Dienogest (Rec.INN registered by WHO)

Dosage Form

Normetrilla

Tablets 2 mg: 28 or 84 pcs.

Dosage Form, Packaging, and Composition

Tablets are round, biconvex, and white in color.

Excipients: lactose monohydrate, corn starch, povidone K30, magnesium stearate.

28 pcs. – blisters (1) – cardboard packs.
28 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Gestagen

Pharmacotherapeutic Group

Sex hormones and modulators of the genital system; progestogens; pregnadiene derivatives

Pharmacological Action

Mechanism of action

Dienogest affects endometriosis by suppressing the trophic effects of estrogens on the eutopic and ectopic endometrium, due to a reduction in estrogen production in the ovaries and a decrease in their plasma concentration.

With prolonged use, it causes initial decidualization of endometrial tissue followed by atrophy of endometriotic lesions.

Pharmacodynamic effects

Dienogest is a derivative of norethisterone, characterized by antiandrogenic activity approximately one-third that of cyproterone acetate. Dienogest binds to progesterone receptors in the human uterus, having only 10% of the relative affinity of progesterone. Despite its low affinity for progesterone receptors, Dienogest is characterized by a potent progestogenic effect in vivo. Dienogest does not possess significant androgenic, mineralocorticoid, or glucocorticoid activity in vivo.

Clinical efficacy and safety

The benefit of dienogest compared to placebo regarding pelvic pain associated with endometriosis was demonstrated in a clinical trial that included 198 patients over a duration of 3 months. Pelvic pain associated with endometriosis was assessed using a visual analog scale (VAS, 0-100 mm). After 3 months of treatment with dienogest, a statistically significant difference compared to placebo was shown (Δ=12.3 mm; 95% CI: 6.4-18.1; p<0.0001), as well as a clinically significant reduction in pain compared to baseline (mean reduction = 27.4 mm±22.9).

After 3 months of treatment, 37.3% of patients experienced a reduction in the intensity of pelvic pain associated with endometriosis by 50% or more without an increase in the dose of additional analgesic medication they were taking (placebo: 19.8%); 18.6% of patients experienced a reduction in the intensity of pelvic pain associated with endometriosis by 75% or more without an increase in the dose of additional analgesic medication they were taking (placebo: 7.3%).

In the extended open-label phase of this placebo-controlled study, a sustained reduction in pelvic pain associated with endometriosis was observed with treatment duration of up to 15 months.

The results of the placebo-controlled study were confirmed by data obtained during a 6-month study comparing it with a gonadotropin-releasing hormone (GnRH) agonist, which included 252 patients with endometriosis.

In 3 studies involving a total of 252 patients receiving a daily dose of dienogest 2 mg, a significant reduction in endometriotic lesions was demonstrated after 6 months of treatment.

A small study (n=8 per dose group) showed that a daily dose of 1 mg dienogest caused suppression of ovulation after 1 month of treatment. The contraceptive efficacy of dienogest has not been studied in larger trials.

The level of endogenous estrogens is moderately suppressed during treatment with dienogest.

Bone mineral density (BMD) was assessed in 21 adult patients before the start of treatment and after 6 months of drug use; no decrease in the mean BMD value was noted.

In 29 patients receiving leuprorelin acetate (LA), over the same period, a mean decrease of 4.04%±4.84 was observed (Δ between groups = 4.29%; 95% CI: 1.93-6.66; p<0.0003).

Safety data in adolescents

The safety of dienogest regarding BMD was investigated in an uncontrolled clinical trial over 12 months involving 111 adolescents (12-18 years old, post-menarche) with clinically suspected or confirmed endometriosis. The mean relative change in lumbar spine BMD (vertebrae L2 – L4) from baseline in 103 patients was -1.2%. In the group of patients who experienced a decrease in BMD, this parameter was measured again 6 months after the end of treatment during the extended follow-up period, and the analysis showed an increase in BMD level to -0.6%.

During the use of dienogest for up to 15 months, no significant effect of the drug on standard laboratory parameters, including hematology, blood chemistry, liver enzyme levels, lipids, and glycated hemoglobin, was observed.

Long-term use safety data

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

A total of 3,023 women started taking dienogest at a dose of 2 mg, and 3,371 patients started taking other approved drugs for endometriosis. The total adjusted hazard ratio for new cases of anemia comparing patients receiving Dienogest and patients receiving other approved drugs for endometriosis was 1.1 (95% CI: 0.4-2.6). The adjusted hazard ratio for the development of depression comparing dienogest and other approved drugs for endometriosis was 1.8 (95% CI: 0.3-9.4). An increased risk of depression in patients taking Dienogest compared to patients taking other approved drugs for endometriosis cannot be ruled out.

Pharmacokinetics

Absorption

After oral administration, Dienogest is rapidly and almost completely absorbed. The C_max in plasma, which is 47 ng/ml, is reached approximately 1.5 hours after a single oral dose. The bioavailability is about 91%. The pharmacokinetics of dienogest in the dose range from 1 to 8 mg is dose-dependent.

Distribution

Dienogest binds to albumin in plasma and does not bind to sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG). 10% of the total plasma concentration of the substance is in the form of free steroid, while about 90% is non-specifically bound to albumin. The apparent V_d of dienogest is 40 L.

Metabolism

Dienogest is almost completely metabolized, primarily via hydroxylation, forming several largely inactive metabolites. Based on in vitro and in vivo study results, the main enzyme involved in the metabolism of dienogest is CYP3A4. Metabolites are eliminated very rapidly, so the predominant fraction in plasma is unchanged Dienogest. The metabolic clearance rate (Cl/F) from plasma is 64 ml/min.

Excretion

The plasma concentration of dienogest decreases in a biphasic manner. The T_1/2 in the terminal phase is approximately 9-10 hours. After oral administration of a dose of 0.1 mg/kg, Dienogest is excreted as metabolites by the kidneys and via the intestine in a ratio of approximately 3:1. The T_1/2 of renal metabolites is 14 hours. After oral administration, approximately 86% of the administered dose is excreted within 6 days, with the majority excreted within the first 24 hours, primarily by the kidneys.

Pharmacokinetic-pharmacodynamic relationship

The pharmacokinetics of dienogest is independent of SHBG levels. The plasma concentration of dienogest after daily administration increases by approximately 1.24-fold, reaching C_ss after 4 days of administration. The pharmacokinetics of dienogest after multiple administrations can be predicted based on the pharmacokinetics after a single dose.

Indications

• Treatment of endometriosis in adults and children aged 12 to 18 years after menarche.

ICD codes

Dosage Regimen

The drug is taken orally, 1 tablet once a day without interruption, preferably at the same time every day, if necessary with water or another liquid.

Before starting Normetrilla, hormonal contraception should be discontinued. If contraception is required, non-hormonal methods of contraception (e.g., barrier method) should be used.

Normetrilla can be started on any day of the menstrual cycle. Tablets must be taken continuously regardless of vaginal bleeding. After finishing the tablets from one package, start taking from the next package without a break in taking the drug.

If tablets are missed and in case of vomiting and/or diarrhea (if this occurs within 3-4 hours after taking the tablet), the effectiveness of Normetrilla may decrease.

If one or more tablets are missed, the woman should take one tablet as soon as she remembers, and then continue taking the tablets at the usual time the next day. One tablet should also be taken instead of the tablet that was not absorbed due to vomiting or diarrhea.

There is no relationship between taking the drug and food intake.

Special patient groups

Elderly patients

There is no relevant basis for the use of Normetrilla in elderly patients.

Patients with impaired liver function

Normetrilla is contraindicated in severe liver diseases currently or in history (see section “Contraindications”).

Patients with impaired renal function

There are no data indicating a need for dose adjustment in patients with impaired renal function.

Children

The safety and efficacy of Normetrilla in children aged 0 to 12 years have not been established. Normetrilla can be used in children from 12 years of age after menarche. The dosage regimen for children from 12 to 18 years does not differ from the dosage regimen for adults.

Adverse Reactions

Summary of the safety profile

Adverse reactions occur more frequently in the first months of taking dienogest, and their number decreases over time. The most common adverse reactions include: vaginal bleeding (including spotting, metrorrhagia, menorrhagia, irregular bleeding), headache, breast discomfort, depressed mood, and acne.

Tabulated summary of adverse reactions

According to WHO, side effects are classified according to their frequency of occurrence as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from the available data). The frequency analysis is based on pooled data from 4 clinical trials involving 332 patients (100%).

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

The use of dienogest is contraindicated in the presence of any of the conditions listed below, some of which are common to all drugs containing only a progestogenic component. If any of these conditions develop during the use of dienogest, treatment with the drug should be discontinued immediately.

• Hypersensitivity to dienogest or to any of the excipients included in the drug;
• Acute thrombophlebitis, current venous thromboembolism;
• Heart and arterial diseases based on atherosclerotic vascular lesions (including coronary artery disease, myocardial infarction, stroke, and transient ischemic attack) currently or in history;
• Diabetes mellitus with vascular complications;
• Severe liver diseases currently or in history (in the absence of normalization of liver function tests);
• Liver tumors (benign or malignant) currently or in history;
• Identified or suspected hormone-dependent malignant tumors, including breast cancer;
• Vaginal bleeding of unknown origin;
• History of cholestatic jaundice of pregnancy;
• Children under 12 years of age (before menarche).

With caution

History of depression, history of ectopic pregnancy, arterial hypertension, chronic heart failure, migraine with aura, diabetes mellitus without vascular complications, hyperlipidemia, history of deep vein thrombophlebitis, history of venous thromboembolism (see section “Special Instructions”).

Use in Pregnancy and Lactation

Pregnancy

Experience with the use of dienogest in pregnant women is very limited. No reproductive toxicity, genotoxicity, or carcinogenicity was identified in animal studies. Dienogest should not be prescribed to pregnant women, as there is no need for endometriosis treatment during pregnancy.

Breastfeeding period

The use of dienogest during breastfeeding is not recommended, as animal studies have shown that Dienogest passes into breast milk. The decision to discontinue breastfeeding or to refrain from taking dienogest is made based on an assessment of the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

According to available data, ovulation is suppressed in most patients during the use of dienogest. However, Dienogest is not a contraceptive. The contraceptive efficacy of dienogest has not been studied; however, as shown in one study, a dienogest dose of 2 mg suppressed ovulation after 1 month of treatment in 20 women.

According to available data, the physiological menstrual cycle is restored within 2 months after discontinuation of dienogest.

Use in Hepatic Impairment

Normetrilla is contraindicated in severe liver diseases currently or in history (in the absence of normalization of liver function tests); liver tumors (benign or malignant) currently or in history.

Use in Renal Impairment

There are no data indicating a need for dose adjustment in patients with impaired renal function.

Pediatric Use

The safety and efficacy of Normetrilla in children aged 0 to 12 years have not been established. Normetrilla can be used in children from 12 years of age after menarche.

Geriatric Use

There are no relevant grounds for the use of Normetrilla in elderly female patients.

Special Precautions

Before starting the use of Dienogest, pregnancy must be excluded. During the use of Dienogest, if contraception is necessary, patients are advised to use non-hormonal contraceptive methods (for example, barrier methods).

The likelihood of ectopic pregnancy is higher in patients using progestogen-only preparations for contraception compared to patients using combined oral contraceptives. Therefore, for women with a history of ectopic pregnancy or with fallopian tube obstruction, the benefit-risk ratio should be assessed before using Dienogest.

Since Dienogest is a progestogen-only preparation, it can be assumed that the special instructions and precautions established for other preparations of this type are also relevant for Dienogest, although not all of these warnings have been confirmed in the course of clinical studies of Dienogest.

If any of the conditions or risk factors listed below are present or worsening, an individual assessment of the benefit-risk ratio should be performed before starting or continuing the use of Dienogest.

Circulatory Disorders

Epidemiological studies have provided insufficient evidence to confirm an association between the use of progestogen-only preparations and an increased risk of myocardial infarction or cerebral thromboembolism. The risk of cardiovascular episodes and cerebrovascular disorders is more likely associated with increasing age, arterial hypertension, and smoking. The risk of stroke in women with arterial hypertension may slightly increase while using progestogen-only preparations. Some studies indicate the possibility of a statistically insignificant increase in the risk of venous thromboembolism (VTE, DVT, PE) associated with the use of progestogen-only preparations. Recognized risk factors for the development of venous thromboembolism (VTE) include a relevant family history (VTE in a sibling or parent at a relatively young age), age, obesity, prolonged immobilization, major surgery, or serious trauma. In case of prolonged immobilization, it is recommended to discontinue the use of Dienogest (for planned surgery at least 4 weeks before it) and resume the use of the preparation only 2 weeks after full mobility is restored.

The increased risk of thromboembolism in the postpartum period should be taken into account. If arterial or venous thrombosis develops or is suspected, the use of the preparation should be stopped immediately.

Tumors

A meta-analysis of 54 epidemiological studies revealed a small increase in the relative risk (RR=1.24) of breast cancer development in women who were using oral contraceptives at the time of the study, predominantly estrogen-progestogen preparations. This increased risk gradually disappears within 10 years after stopping the use of combined oral contraceptives (COCs). Since breast cancer is rare in women under 40 years of age, a certain increase in the number of such diagnoses in women currently taking COCs or who have used COCs in the past is small relative to the overall risk rate for breast cancer. The risk of detecting breast cancer in women using progestogen-only preparations is possibly similar in magnitude to the corresponding risk associated with the use of COCs. However, data related to progestogen-only preparations are based on much smaller populations of women taking them and are therefore less convincing than data for COCs. Establishing a causal relationship based on these studies is not possible. The identified pattern of increasing risk may be due to earlier diagnosis of breast cancer in women taking oral contraceptives, the biological effect of oral contraceptives, or a combination of both factors. Women who have used hormonal contraceptives are diagnosed with earlier clinical stages of breast cancer than women who have never used them.

In rare cases, during the use of hormonal substances similar to that contained in Normetrilla, benign, and even more rarely, malignant liver tumors have been observed. In some cases, these tumors have led to life-threatening intra-abdominal bleeding. If a woman taking Dienogest experiences severe pain in the upper abdomen, has an enlarged liver, or shows signs of intra-abdominal bleeding, the possibility of a liver tumor should be considered in the differential diagnosis.

Changes in Bleeding Patterns

In most women, the use of Dienogest affects the nature of menstrual bleeding.

Uterine bleeding may increase during the use of Dienogest, for example, in women with adenomyosis or uterine leiomyoma. Heavy and prolonged bleeding can lead to anemia (in some cases severe). In such cases, the discontinuation of Normetrilla should be considered.

Changes in Bone Mineral Density (BMD)

The physician should weigh the benefit of the preparation against the possible risks for each patient, also taking into account the possibility of risk factors for osteoporosis (e.g., dysmetabolic osteopathy, family history of osteoporosis, low body mass index or eating disorders, long-term use of medications that can reduce bone mass, such as anticonvulsants or glucocorticoids, previous fractures due to minor trauma, alcohol abuse and/or smoking). It is important for women of all ages to consume calcium and vitamin D, regardless of adherence to a specific diet or the use of vitamin supplements.

No decrease in BMD was noted in adult patients.

Children

When Dienogest was used in adolescents (12-18 years) over 12 months of treatment, a decrease in lumbar spine BMD was observed by an average of 1.2%. After discontinuation of treatment, BMD in these patients increased again.

The decrease in BMD is of particular concern during adolescence and late adolescence, as this is a particularly important period for bone growth. It is unknown whether the decrease in BMD affects the peak bone mass in this population and increases the risk of fractures later in life.

Other Conditions

Patients with a history of depression require careful observation. If depression recurs in a severe form, the preparation should be discontinued. In general, Dienogest does not appear to affect blood pressure in women with normal blood pressure. However, if persistent clinically significant arterial hypertension occurs during the use of Dienogest, it is recommended to discontinue the preparation and initiate antihypertensive treatment. If cholestatic jaundice and/or cholestatic pruritus recur, which first occurred during pregnancy or previous use of sex hormones, Dienogest must be discontinued.

Dienogest may have a slight effect on peripheral insulin resistance and glucose tolerance. Women suffering from diabetes mellitus, especially those with a history of gestational diabetes, require careful observation during the use of Dienogest.

In some cases, chloasma may occur, especially in women with a history of chloasma during pregnancy. Women prone to developing chloasma should avoid sun exposure or ultraviolet radiation during the use of Dienogest. During the use of Dienogest, persistent ovarian follicles (often called functional ovarian cysts) may occur. In most cases, the presence of such follicles is asymptomatic, although some may be accompanied by pelvic pain.

Medical Examination

Before starting or resuming the use of Dienogest, a detailed medical history should be taken and a physical and gynecological examination should be performed. The frequency and nature of such examinations should be based on existing standards of medical practice with necessary consideration of the individual characteristics of each patient (but not less than once every 3-6 months) and should include blood pressure measurement, assessment of the condition of the mammary glands, abdominal and pelvic organs, including cervical cytology.

Excipients

Normetrilla contains lactose monohydrate. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this preparation.

Effect on Ability to Drive and Operate Machinery

No negative effect of Dienogest on the ability to drive and operate machinery has been noted; however, patients who experience impaired concentration during the adaptation period (the first 3 months of using the preparation) should exercise caution.

Overdose

No serious cases of overdose have been reported.

Symptoms nausea, vomiting, spotting, or metrorrhagia.

Treatment there is no specific antidote; symptomatic treatment should be carried out.

Drug Interactions

Effect of Other Medicinal Products on Dienogest

Progestogens, including Dienogest, are metabolized primarily with the participation of cytochrome P450 3A4 (CYP3A4) isoenzymes, located both in the intestinal mucosa and in the liver. Therefore, inducers or inhibitors of CYP3A4 can affect the metabolism of progestogenic preparations.

Increased clearance of sex hormones due to enzyme induction can lead to a decrease in the therapeutic effect of Dienogest and also cause adverse reactions, for example, changes in the nature of uterine bleeding.

Decreased clearance of sex hormones due to enzyme inhibition can increase the exposure of Dienogest and cause adverse reactions.

Substances that increase the clearance of sex hormones (reduced efficacy through enzyme induction)

Phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly oxcarbazepine, topiramate, felbamate, griseofulvin, and preparations containing St. John’s wort.

Enzyme induction is generally noted a few days after the start of therapy, maximum induction is noted within a few weeks and can then persist for up to 4 weeks after discontinuation of therapy.

The effect of the CYP3A4 inducer rifampicin was studied in healthy postmenopausal women. With the simultaneous use of rifampicin with tablets containing estradiol valerate/Dienogest, a significant decrease in the steady-state concentration and systemic exposure of Dienogest was observed. The systemic exposure of Dienogest at steady state, determined by the AUC_{(0-24 h)} value, was reduced by 83%.

Substances with variable effects on the clearance of sex hormones

When used concomitantly with sex hormones, many drugs for the treatment of HIV and hepatitis C and non-nucleoside reverse transcriptase inhibitors can increase or decrease plasma concentrations of progestins. In some cases, such changes may be clinically significant.

Substances that decrease the clearance of sex hormones (enzyme inhibitors)

Dienogest is a substrate of cytochrome P450 (CYP) 3A4.

Highly active inhibitors and inhibitors of CYP3A4 with moderate activity, for example, azole antifungals (itraconazole, voriconazole, fluconazole), verapamil, macrolides (clarithromycin, erythromycin), diltiazem, and grapefruit juice may lead to an increase in plasma concentrations of the progestogen.

In one study investigating the effect of CYP3A4 inhibitors (ketoconazole, erythromycin), the steady-state plasma concentrations of estradiol valerate and Dienogest were increased. With simultaneous use with the potent inhibitor ketoconazole, the steady-state AUC_{(0-24 h)} for Dienogest increased by 2.86 times. With simultaneous use with the moderate CYP3A4 inhibitor erythromycin, the steady-state AUC_{(0-24 h)} for Dienogest increased by 1.62 times. The clinical significance of these interactions is not clear.

Effect of Dienogest on Other Medicinal Products

Based on in vitro inhibition data, clinically significant interaction of Dienogest with other medicinal products metabolized via cytochrome P450 system enzymes is unlikely.

Interaction with Food

Food intake with a high fat content did not affect the bioavailability of Dienogest.

Other Interactions

The use of progestogens may affect the results of some laboratory tests, including biochemical parameters of liver, thyroid, adrenal, and kidney function, plasma concentrations of (carrier) proteins, for example, lipid/lipoprotein fractions, parameters of carbohydrate metabolism, and coagulation parameters.

Storage Conditions

The preparation should be stored in the original packaging (in the carton) at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life is 2 years.

Dispensing Status

The preparation is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.