Diemeno

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIEMONO® (DIEMONO)

Composition:

Active substance: dienogest;

1 tablet contains 2 mg of dienogest;

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

Pharmaceutical form. Film-coated tablets.

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

Pharmacotherapeutic group.

Sex gland hormones and drugs used in pathologies of genital organs. Progestogens. Pregnadiene derivatives. Dienogest. ATC code G03D B08.

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 initially to decidualization of endometrial tissue followed by atrophy of endometriotic lesions.

Efficacy Data

The superiority of dienogest 2 mg compared to placebo was demonstrated in a 3-month study involving 198 patients with endometriosis. Pelvic pain associated with endometriosis was assessed using a visual analog scale (0–100 mm). After 3 months of treatment with dienogest 2 mg, a statistically significant difference compared to placebo was observed (∆ = 12.3 mm; 95% CI: 6.4–18.1; p < 0.0001), along with clinically meaningful pain reduction compared to baseline (mean reduction = 27.4 mm ± 22.9).

After 3 months of treatment, a 50% or greater reduction in pelvic pain associated with endometriosis was achieved in 37.3% of patients receiving dienogest 2 mg (placebo: 19.8%), without concomitant increase in analgesic dose. A 75% or greater reduction in pelvic pain associated with endometriosis, also without concomitant increase in analgesic dose, was achieved in 18.6% of patients receiving dienogest 2 mg (placebo: 7.3%).

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

Results from placebo-controlled trials were confirmed by findings from a 6-month active-controlled study comparing dienogest to a gonadotropin-releasing hormone agonist in 252 patients with endometriosis.

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

In a small study (n = 8 per dosage group), administration of dienogest at a daily dose of 1 mg was shown to suppress ovulation within 1 month of therapy. The contraceptive efficacy of dienogest 2 mg has not been evaluated in large-scale studies.

Safety Data

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

Currently, long-term data on bone mineral density (BMD) and fracture risk in patients receiving dienogest 2 mg are not available. BMD was evaluated in 21 adult patients before and after 6 months of dienogest 2 mg treatment; no significant decrease in mean BMD was observed.

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

No significant impact on standard laboratory parameters (including blood counts, blood biochemistry, liver enzyme levels, lipid levels, and HbA1c) was observed during 15 months of treatment with dienogest 2 mg (n = 168).

Safety in Adolescents

The safety of dienogest 2 mg regarding BMD was evaluated in a 12-month uncontrolled clinical study involving 111 adolescent patients (aged 12 to <18 years) with clinically suspected or confirmed endometriosis. The mean relative change in lumbar spine (L2–L4) BMD compared to baseline in 103 patients who underwent BMD measurement was +1.2%. Repeat measurement 6 months after treatment completion in a subgroup of patients with low baseline BMD indicated an increase in BMD to –0.6%.

Safety of Long-Term Therapy

A long-term post-marketing active surveillance study was conducted to assess the incidence or worsening of clinically significant depression and anemia. Overall, 27,840 women with recently initiated hormonal therapy for endometriosis were observed for up to 7 years.

A total of 3023 women initiated treatment with dienogest 2 mg, and 3371 women initiated treatment with other approved endometriosis therapies. The overall adjusted risk ratio for anemia between patients taking dienogest and those taking other approved endometriosis medications was 1.1 (95% CI: 0.4–2.6). The adjusted risk ratio for depression between patients taking dienogest and those taking other approved endometriosis medications was 1.8 (95% CI: 0.3–9.4). A slightly increased risk of depression in patients taking dienogest compared to other approved endometriosis treatments cannot be ruled out.

Pharmacokinetics

Absorption

Following oral administration, dienogest is rapidly and almost completely absorbed. Peak 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 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 nonspecifically bound to albumin.

The apparent volume of distribution of dienogest is 40 L.

Biotransformation

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 dienogest metabolism. Elimination of these metabolites occurs very rapidly, while unchanged dienogest remains the predominant fraction in plasma.

Plasma clearance rate is 64 mL/min.

Elimination

Serum dienogest levels decline in a biphasic manner. The terminal half-life is approximately 9–10 hours. Dienogest is excreted in the form of metabolites in urine and feces in a ratio of approximately 3:1 after an oral dose of 0.1 mg/kg. The half-life of metabolites in urine is 14 hours. Approximately 86% of the administered dose is excreted within a six-day period after oral administration, with most of this amount eliminated within the first 24 hours, primarily via urine.

Steady-State Conditions

The pharmacokinetics of dienogest are not influenced by SHBG levels. With daily administration, serum concentrations increase by a factor of 1.24, reaching steady state after 4 days of treatment. The pharmacokinetics of dienogest after repeated administration of 2 mg can be predicted based on single-dose pharmacokinetic data.

Patients with Renal Impairment

No specific studies with dienogest 2 mg have been conducted in patients with impaired renal function.

Patients with Hepatic Impairment

No specific studies with dienogest 2 mg have been conducted in patients with impaired hepatic function.

Preclinical Safety Data

Preclinical studies do not indicate a specific risk for humans based on standard repeated-dose toxicity, genotoxicity, carcinogenicity, and reproductive toxicity assessments. However, it should be noted that sex steroids may promote the growth of certain hormone-dependent tissues and tumors.

Clinical characteristics.

Indications.

Treatment of endometriosis.

Contraindications.

Dienomon® should not be used if any of the conditions or diseases listed below are present. This information is partly derived from the use of other drugs containing only progestogens. If any of these conditions or diseases develops during treatment with Dienomon®, the drug should be discontinued immediately:

• Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition";
• Active venous thromboembolism;
• Arterial or cardiovascular diseases currently or in medical history (e.g., myocardial infarction, stroke, ischemic heart disease);
• Diabetes mellitus with vascular complications;
• Severe liver disease currently or in medical history, until liver function tests return to normal;
• Liver tumors currently or in medical history (benign or malignant);
• Known or suspected hormonally-dependent malignant tumors;
• Vaginal bleeding of unknown etiology.

Interaction with other medicinal products and other forms of interaction.

Note: To identify possible interactions, the instructions for medical use of drugs currently taken by the patient should be consulted.

Effect of other drugs on Dienomon®

Metabolism of progestogens, including dienogest, is primarily mediated 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 Dienomon® and lead to adverse reactions, such as changes in menstrual bleeding patterns.

Reduced clearance of sex hormones due to enzyme inhibition may result in increased exposure to dienogest, potentially leading to the development of adverse reactions.

• Substances that increase clearance of sex hormones (reduced efficacy due to enzyme induction):

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

The effect of the CYP3A4 inducer rifampicin was studied in a trial involving healthy postmenopausal women. Concomitant administration of rifampicin and estradiol valerate/dienogest tablets resulted in a significant reduction in the steady-state concentration and systemic exposure of both 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 sex hormone clearance.

Concomitant use of sex hormones with numerous combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations of hepatitis C virus (HCV) inhibitors, may result in increased or decreased plasma levels of progestin. The net effect of these changes may be clinically significant in some cases.

• Substances that reduce 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. When co-administered with the potent CYP3A4 inhibitor ketoconazole, a 2.9-fold increase in the steady-state AUC(0–24 hours) of dienogest was observed. 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 Dienomon® on other medicinal products

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

Interaction with food

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

Laboratory tests

The use of progestogens may influence the results of certain laboratory tests, including liver and thyroid function, kidney and adrenal gland function, plasma protein levels (e.g., corticosteroid-binding globulin), lipid/lipoprotein fractions, carbohydrate metabolism parameters, and coagulation and fibrinolysis parameters. These changes generally remain within laboratory reference ranges.

Special precautions for use

Warnings

Since DIENONE® contains only a progestogen, it is considered that special precautions and safety measures applicable to progestogen-only preparations also apply to DIENONE®.

An individual risk-benefit assessment should be performed prior to initiating or continuing therapy with DIENONE® in the presence of or if there is worsening of any of the conditions or risk factors listed below.

Severe uterine bleeding

Uterine bleeding, for example in women with adenomyosis or uterine leiomyoma, may be exacerbated by the use of DIENONE®. If bleeding is heavy and persistent, it may lead to anemia (in some cases severe). In the event of anemia development, discontinuation of DIENONE® should be considered.

Changes in bleeding pattern

In most patients, treatment with 2 mg of dienogest leads to changes in the pattern of menstrual bleeding (see section "Adverse reactions").

Impaired circulation

Epidemiological studies provide little evidence of an association between progestogen-only preparations and an increased risk of myocardial infarction or cerebral thromboembolism. The risk of cardiovascular and cerebrovascular events is somewhat related to age, arterial hypertension, and smoking. In women with 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 (deep vein thrombosis, pulmonary artery embolism) associated with the use of progestogen-only preparations. Well-known risk factors for venous thromboembolism (VTE) include personal or family history (e.g., VTE cases in close relatives or parents at a relatively young age), age, obesity, prolonged immobilization, major surgery, or trauma. In case of prolonged immobilization, use of DIENONE® should be discontinued (at least 4 weeks prior to planned surgery) and not resumed until at least 2 weeks after full mobility is restored.

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

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

Neoplasms

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 (OC), primarily combined estrogen-progestogen products. This increased risk gradually disappears within 10 years after discontinuation of combined oral contraceptives (COC). 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 in relation to the overall risk of breast cancer. The risk of detecting breast cancer is similar in women using progestogen-only preparations or COCs. However, information regarding progestogen-only preparations is based on a much smaller number of users and is 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 drugs, or a combination of both factors. A trend has been observed that breast cancer detected in women who have ever used OCs is clinically less aggressive than in women 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 that contained in DIENONE®. In some cases, such tumors have led to life-threatening intra-abdominal hemorrhage. In the event 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 DIENONE®.

Osteoporosis

Changes in bone mineral density (BMD).

The use of 2 mg dienogest for 12 months in adolescent therapy (12 – <18 years) has been associated with a decrease in mean bone mineral density (BMD) in 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 from –6% to 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 from –9% to 6% [95% CI: –1.20% to 0.06%, n=60]). Reduced bone mineral density is of particular concern during adolescence and early puberty, which are critical periods for bone growth. It is unknown whether the reduction in BMD in this population will lead to reduced peak bone mass and increased fracture risk in later life (see sections "Dosage and administration" and "Pharmacodynamics").

A careful benefit-risk assessment is required before initiating therapy with DIENONE® in patients at increased risk of osteoporosis, as endogenous estrogen levels are moderately reduced during treatment with this medicinal product (see section "Pharmacodynamics").

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

Other conditions

Patients with a history of depression should be closely monitored, and the drug should be discontinued if pronounced depressive symptoms develop.

Dienogest generally does not affect blood pressure in normotensive women. If clinically significant, persistent hypertension develops during treatment with DIENONE®, the drug should be discontinued and hypertension treated.

Further use of DIENONE® should be discontinued in case of recurrence of cholestatic jaundice and/or pruritus that occurred during pregnancy or previous use of sex steroids.

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 DIENONE®.

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 DIENONE®.

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

During treatment with DIENONE®, 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.

DIENONE® contains lactose and sodium.

One tablet contains 48.6 mg of lactose monohydrate. DIENONE® should not be administered to patients with rare hereditary conditions of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

This medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy

Limited data are available on the use of dienogest in pregnant women.

Animal studies do not indicate direct or indirect adverse effects with regard to reproductive toxicity (see section "Pharmacokinetics").

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

Breastfeeding

Use of DIENONE® during breastfeeding is not recommended.

It is unknown whether dienogest passes into human breast milk. Animal data indicate that dienogest is excreted into the milk of rats.

A decision should be made whether to discontinue breastfeeding or to discontinue DIENONE® therapy, taking into account the benefit of breastfeeding for the child and the necessity of therapy for the woman.

Fertility

Based on available data, ovulation is suppressed in most patients during treatment with DIENONE®. However, DIENONE® 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, menstrual cycles return to normal within 2 months after discontinuation of DIENONE® treatment.

Ability to influence reaction speed when driving or operating machinery

No effects on the ability to drive or operate machinery have been observed in patients taking dienogest-containing preparations.

Method of Administration and Dosage

Method of Administration

Oral administration.

Dosage Regimen

Take 1 tablet daily without interruption at approximately the same time each day, swallowing with a small amount of liquid. Tablets may be taken independently of food intake.

Tablets should be taken regularly regardless of vaginal bleeding. As soon as the tablets from one pack are finished, begin taking tablets from the next pack without any break in medication use.

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

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

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 Dieno® may be reduced. If one or more tablets are missed, take 1 tablet as soon as remembered, then continue taking the tablets at the usual time the next day. A tablet not absorbed due to vomiting or diarrhea should be replaced with another tablet.

Elderly Patients

There are no appropriate indications for the use of Dieno® in elderly women.

Patients with Hepatic Impairment

Use of Dieno® is contraindicated in patients with severe liver disease, whether present or in medical history (see section "Contraindications").

Patients with Renal Impairment

There is no evidence requiring dose adjustment in patients with renal impairment.

Children

Dieno® is not indicated for use in children and adolescents before menarche.

The safety and efficacy of 2 mg dienogest tablets were evaluated in an uncontrolled clinical trial lasting over 12 months, which included 111 adolescent patients (aged 12 to < 18 years) with clinical suspicion of endometriosis or confirmed endometriosis diagnosis (see sections "Special Instructions" and "Pharmacodynamics").

Overdose

Acute toxicity studies of dienogest do not indicate a risk of acute adverse reactions following unintentional ingestion of several daily therapeutic doses. There is no specific antidote. Doses of dienogest up to 20–30 mg per day (10–15 times the dose contained in Dieno®) administered for more than 24 weeks were very well tolerated.

Adverse Reactions

Adverse reactions are listed according to MedDRA. The most appropriate MedDRA term has been used to describe a particular reaction and related conditions.

Adverse reactions most commonly occur during the first months after initiation of treatment with Dienomon® and usually subside with continued therapy. Changes in the pattern of menstrual bleeding such as spotting, irregular bleeding, or amenorrhea may occur. The following adverse reactions have been reported in patients treated with 2 mg of dienogest.

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

Additionally, the majority of patients receiving 2 mg of dienogest experience changes in the pattern of menstrual bleeding. The nature of menstrual bleeding was 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 with 2 mg of dienogest, 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 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%), and normal menstrual bleeding, i.e., not falling into any of the previous categories (22.8%). Changes in the pattern of menstrual bleeding were only occasionally reported as adverse reactions by patients (see table of adverse reactions).

Table 1 lists adverse reactions by MedDRA System Organ Class (SOC) reported during treatment with 2 mg of dienogest and their frequency. Within each group, adverse reactions are listed in order of decreasing frequency.

Frequency is based on pooled data from four clinical trials involving 332 patients (100%).

Table 1

Adverse reactions, Phase III clinical trials, N = 332

Organ systems (MedDRA)	Common (≥ 1/100 - < 1/10)	Uncommon (≥ 1/1000 - < 1/100)
Blood and lymphatic system disorders		anaemia
Metabolism and nutrition disorders	weight increased	weight decreased, increased appetite
Psychiatric disorders	depressed mood, sleep disorders, nervousness, loss of libido, mood changes	anxiety, depression, sudden mood swings
Nervous system disorders	headache, migraine	autonomic nervous system imbalance, attention disturbance
Eye disorders		dry eyes
Ear and labyrinth disorders		tinnitus
Cardiac disorders		non-specific circulatory disorders, palpitations
Vascular disorders		arterial hypotension
Respiratory, thoracic and mediastinal disorders		dyspnoea
Gastrointestinal disorders	nausea, abdominal pain, flatulence, bloating, vomiting	diarrhoea, constipation, abdominal discomfort, gastrointestinal inflammation, gingivitis
Skin and subcutaneous tissue disorders	acne, alopecia	dry skin, hyperhidrosis, pruritus, hirsutism, onychoclasis, dandruff, dermatitis, abnormal hair growth, photosensitivity reactions, pigmentation changes
Musculoskeletal and connective tissue disorders	back pain	bone pain, muscle cramps, limb pain, heaviness in limbs
Renal and urinary disorders		urinary tract infection
Reproductive system and breast disorders	breast discomfort, ovarian cyst, hot flushes, uterine/vaginal bleeding, including spotting	vaginal candidiasis, vulvovaginal dryness, genital discharge, pelvic pain, atrophic vaginitis, breast enlargement, fibrocystic breast disease, breast tenderness
General disorders and administration site conditions	asthenic conditions, irritability	oedema

Reduction in bone mineral density

In an uncontrolled clinical study involving 111 female adolescents (aged 12 to <18 years) receiving treatment with 2 mg of dienogest, bone mineral density (BMD) was measured in 103 patients. A decrease in BMD of the lumbar spine (L2–L4) 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 suspected adverse reactions after marketing authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at https://aisf.dec.gov.ua.

Shelf life. 4 years.

Storage conditions.

No special storage conditions required. Keep out of reach and sight of children.

Packaging.

28 tablets per blister; 1, 3, or 6 blisters per carton.

Prescription status. Prescription only.

Manufacturer: mibe GmbH & Co. KG.

Manufacturer's address and location of operation:

Muenchener Strasse 15, Brehna, Saxony-Anhalt, 06796, Germany.