Daivonex

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

Composition:

Active substance: dienogest; 1 tablet contains 2 mg of dienogest.

Excipients: lactose monohydrate; corn starch; povidone K-30; magnesium stearate (vegetable).

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white, round tablets.

Pharmacotherapeutic group. Sex gland hormones and drugs used in pathologies of the 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 endometrial tissue. 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 over placebo was demonstrated in a 3-month study involving 198 patients with endometriosis. Pelvic pain associated with endometriosis was measured using a visual analog scale (0–100 mm). After 3 months of treatment 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 in pelvic pain associated with endometriosis by 50% or more was achieved in 37.3% of patients receiving dienogest (placebo: 19.8%), without a corresponding increase in the dose of concomitant analgesics; a reduction in pelvic pain by 75% or more (also without increased analgesic use) was achieved in 18.6% of patients receiving dienogest (placebo: 7.3%).

An open-label extension of this placebo-controlled study showed continuous reduction in endometriosis-associated pelvic pain with treatment lasting 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.

Three studies involving 252 patients receiving dienogest at 2 mg daily demonstrated a significant reduction in endometriotic lesions after 6 months of treatment.

In a small study (n=8 per dose group), administration of dienogest at 1 mg daily resulted in absence of ovulation after 1 month of therapy. The contraceptive efficacy of dienogest has not been evaluated in larger studies.

Safety data

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

Currently, long-term data on bone mineral density (BMD) and fracture risk in patients using dienogest are not available. BMD was assessed in 21 adult patients before and after 6 months of treatment with dienogest. No significant decrease in mean BMD was observed. In 29 patients receiving leuprorelin acetate, a mean decrease of 4.04% ± 4.84 was recorded over the same period (Δ between groups: 4.29%; 95% CI: 1.93–6.66; p<0.0003).

No significant effects on standard laboratory parameters—including blood counts, blood biochemistry, liver enzyme levels, lipid levels, and HbA1c—were observed during 15 months of treatment with dienogest (N = 168).

Safety data in adolescents

The safety of dienogest regarding BMD was evaluated in an uncontrolled 12-month 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 from baseline to end of treatment in 103 patients was -1.2%. Repeat measurements 6 months after treatment completion in a subgroup with decreased BMD values showed an increase in BMD to -0.6%.

Preclinical safety data

Preclinical 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 patients received other endometriosis-approved medications. The overall adjusted risk ratio for new-onset anemia in patients 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 patients taking dienogest compared to those on other endometriosis-approved medications was 1.8 (95% CI: 0.3–9.4). A slight increase in the risk of depression in patients taking dienogest compared to those taking other endometriosis-approved medications cannot be ruled out.

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, amounting 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 nonspecifically 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 primary enzyme involved in the metabolism of dienogest. These metabolites are rapidly eliminated such that unchanged dienogest remains the predominant compound in plasma.

The serum clearance rate is 64 mL/min.

Elimination. Serum levels of dienogest decline in a biphasic manner, with a half-life of 9–10 hours. After an oral dose of 0.1 mg/kg, dienogest is excreted in the form of metabolites in urine and feces in a ratio of approximately 3:1. The half-life of metabolites in urine is approximately 14 hours. Within 6 days after oral administration, 86% of the administered dose is eliminated from the body, with most of this amount excreted 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 after 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 renal impairment. The pharmacokinetics of dienogest have not been studied in patients with hepatic impairment.

Clinical characteristics.

Indications.

Treatment of endometriosis.

Contraindications.

The medicinal product Dienage 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 develops for the first time during treatment with dienogest, 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 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 possible interactions, the package leaflets of concomitantly administered medicinal products should be consulted.

Effect of other drugs on dienogest

Progestogens, including dienogest, are metabolized primarily 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 and lead to adverse effects, such as changes in the pattern of menstrual bleeding.

Reduced clearance of sex hormones due to enzyme inhibition may decrease the therapeutic effect of dienogest and lead to the development of adverse reactions.

• Substances that increase the clearance of sex hormones (reduced efficacy via enzyme induction) include, for example: phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly oxcarbazepine, topiramate, felbamate, griseofulvin, and medicinal 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 both 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, 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 the steady-state AUC (0–24 hours) of dienogest. Concomitant administration with the moderate inhibitor erythromycin resulted in a 1.6-fold increase in the steady-state AUC (0–24 hours) of dienogest.

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

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

Laboratory tests

The use of progestogens may affect the results of certain laboratory tests, including 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 for use.

Warnings.

Since Dienella is a progestogen-only preparation, it is considered that special warnings and safety measures regarding the use of progestin-containing drugs also apply to dienogest, although not all warnings and precautions are based on appropriate clinical trial results specifically for this drug.

An individual risk/benefit assessment should be performed before initiating or continuing dienogest treatment if any of the conditions/risk factors listed below worsen or occur for the first time.

Severe uterine bleeding

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

Changes in bleeding pattern

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

Circulatory disorders

Epidemiological studies have provided 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, 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 embolism) associated with the use of progestogen-only preparations. 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 surgical procedures or trauma. In case of prolonged immobilization, dienogest should be discontinued (at least 4 weeks before elective surgery) and not restarted until at least 2 weeks after full recovery.

Increased risk of thromboembolism in the postpartum period should also be considered.

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 stopping 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 who have used progestogen-only preparations or COCs. However, information on progestogen-only preparations is based on data from a much smaller number of users and is therefore less conclusive than data on 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 diagnosed in women who have ever used OCs tends to be less clinically advanced than in those who have never used oral contraceptives.

In isolated cases, women using hormonal substances similar to the one contained in the medicinal product Dienella have developed benign and, even more rarely, malignant liver tumors, which in some cases led to life-threatening intra-abdominal bleeding. In case of complaints of severe epigastric pain, liver enlargement, or signs of intra-abdominal bleeding, the possibility of a liver tumor should be considered in the differential diagnosis for women taking dienogest.

Osteoporosis

Changes in bone mineral density (BMD).

Use of dienogest in adolescents (12–18 years) over a 12-month treatment period was associated with a 1.2% decrease in mean BMD at the lumbar spine (L2–L4). 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 measurement 6 months after treatment 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, with a range between –9% and 6% (95% CI: –1.20% to 0.06%, n=60)).

Bone mineral density changes are of particular importance in adolescents and during early puberty, a critical period of bone growth. It is unknown whether reduced BMD in this population will reduce peak bone mass and increase fracture risk in later life (see sections "Paediatric population" and "Pharmacological properties").

Before initiating treatment, the physician should weigh the benefits of dienogest use against potential risks for each individual adolescent, also considering 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 adults (see section "Pharmacodynamic properties").

In patients at increased risk of osteoporosis, a careful risk/benefit assessment should be performed before starting treatment with Dienella, as endogenous estrogen levels are moderately reduced during dienogest treatment (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 prolonged clinically evident hypertension develops during treatment, Dienella 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 dienogest use.

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

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

During dienogest use, 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 used in geriatric practice.

Lactose

One tablet of Dienella contains 60.93 mg of lactose monohydrate. If a patient has been diagnosed with carbohydrate intolerance, medical advice should be sought before taking the medicinal product Dienella.

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 risks of reproductive toxicity (see section "Pharmacological properties").

The medicinal product Dienella is not recommended for use during pregnancy because there is no need to treat endometriosis during pregnancy.

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

Fertility. Based on available data, ovulation is inhibited in most patients during dienogest treatment. However, the product Dienella 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 dienogest treatment.

Ability to influence reaction rate when driving or operating machinery.

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

Method of Administration and Dosage

Method of Administration

For oral use.

Dosage

Take 1 tablet daily without interruption at approximately the same time each day, 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, the next pack should be started immediately without any break in medication use.

Treatment may be initiated at any time during the menstrual cycle.

Any hormonal contraceptives should be discontinued prior to starting therapy with Dainela. 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 tablet intake, the efficacy of dienogest 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. A tablet not absorbed due to vomiting or diarrhea should similarly be replaced with another tablet.

Additional Information on Use in Specific Patient Populations

Elderly Patients

There are no appropriate indications for the use of dienogest in this patient group.

Hepatic Impairment

The drug 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

Dainela is not indicated for use in children before menarche.

The safety and efficacy of dienogest were evaluated in an uncontrolled 12-month study involving 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 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 dienogest in adolescents over a 12-month treatment period was associated with a mean decrease in bone mineral density (BMD) at the lumbar spine by 1.2%. After discontinuation of treatment, BMD increased again in these patients.

Alterations in bone mineral density are of particular importance during adolescence and early stages of sexual maturation, which represent critical periods of 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 dienogest treatment against the potential risks for each individual adolescent (see sections "Special Warnings and Precautions for Use" and "Pharmacodynamic Properties").

Overdose

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

Adverse reactions

Adverse reactions are described according to MedDRA.

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

The following adverse reactions have been reported during treatment with dienogest. The most commonly 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 nature of menstrual bleeding in most women. The pattern of menstrual bleeding was 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., bleeding 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., bleeding 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).

The table below lists adverse reactions according to MedDRA System Organ Class (SOCs) reported during treatment with dienogest and 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%).

Adverse reactions, Phase III clinical trials, N=332

The following adverse reactions were also observed: follicular persistence, 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 events, 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 treatment with 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 medicine authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicine. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store in the original packaging to protect from light.

Keep out of reach of children.

Packaging. 28 tablets in a blister, 1 blister per carton.

Prescription status.

Prescription only.

Manufacturer. Laboratorios Leon Farma S.A.

Manufacturer's address and location of operations.

Calle La Valentina C/n, Polígono Industrial Navatejera, Villacambres, 24193, Spain.