Marita

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

Composition:

Active substance: micronized dienogest;

1 tablet contains 2 mg of micronized dienogest;

Excipients: lactose monohydrate; povidone K 30; pregelatinized corn starch; microcrystalline cellulose; crospovidone (type A); colloidal anhydrous silicon dioxide; magnesium stearate.

Pharmaceutical form. Tablets.

Main physical and chemical properties: round tablets of white or slightly yellowish color, with "D2" embossed on one side and no embossing on the other side.

Pharmacotherapeutic group. Sex gland hormones and drugs used in pathologies of genital organs. Progestogens. ATC code G03DB08.

Pharmacological properties

Pharmacodynamics

Dienogest is a derivative of nortestosterone with no androgenic activity and with some antiandrogenic activity, approximately one-third that of cyproterone acetate. Dienogest binds to progesterone receptors in the uterus with only 10% relative affinity. Despite its low affinity for progesterone receptors, dienogest exerts a strong progestogenic effect in vivo. Dienogest does not exhibit significant androgenic, mineralocorticoid, or glucocorticoid activity in vivo.

Dienogest affects endometriosis by reducing endogenous estradiol production, thereby suppressing the trophic effects of estradiol on both eutopic and ectopic endometrium. With continuous administration, dienogest creates a hypoestrogenic, hypergestagenic endocrine environment, leading to initial decidualization of endometrial tissue followed by atrophy of endometriotic lesions.

Efficacy data

The superiority of dienogest 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 therapy with dienogest, a statistically significant difference compared to placebo was observed (Δ = 12.3 mm; 95% CI: 6.4–18.1; p<0.0001), as well as a clinically meaningful reduction in pain compared to 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 analgesic; a reduction in pelvic pain by 75% or more (also without a corresponding increase in the dose of concomitant analgesic) 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 up to 15 months.

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

Three studies involving 252 patients receiving dienogest 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 a dose of 1 mg daily resulted in absence of ovulation after 1 month of therapy. Dienogest has not been studied for contraceptive efficacy in larger trials.

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 receiving dienogest are not available. BMD was evaluated in 21 adult patients before and after 6 months of treatment with dienogest. No mean decrease in BMD was observed. In 29 patients receiving leuprorelin acetate, a mean decrease of 4.04% ± 4.84 was observed over the same period (Δ between groups = 4.29%, 95% CI: 1.93–6.66, p<0.0003).

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

Safety data in adolescents

The safety of dienogest regarding BMD was investigated in a 12-month uncontrolled 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 completion of treatment in a subgroup with reduced BMD values showed an increase in BMD to −0.6%.

Non-clinical safety data

Non-clinical safety 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.

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 is present 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, forming predominantly 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 is the predominant component in plasma.

The serum clearance rate is 64 mL/min.

Elimination

The serum concentration of dienogest declines 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 within 6 days, with most of this amount 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 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 impaired renal function.

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

Clinical characteristics.

Indications.

Treatment of endometriosis.

Contraindications.

Marita® must not be used if any of the conditions or diseases listed below are present. This information is partly based on experience with other progestogen-only products. 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, acute cerebrovascular accident, ischemic heart disease).
• Diabetes mellitus with vascular complications.
• Severe liver disease currently present or in medical history, until liver function tests return to normal.
• Benign or malignant liver tumors currently present or in medical history.
• Known or suspected hormonally-dependent malignant tumors.
• Vaginal bleeding of unknown etiology.

Hypersensitivity to the active substance or to any of the excipients of the drug.

Interaction with other medicinal products and other forms of interaction.

Note: To identify possible interactions, the package leaflets of concomitantly administered medicinal products should be consulted.

Effect of other drugs on dienogest

Progestogens, including dienogest, are mainly metabolized by the cytochrome P450 3A4 (CYP3A4) system located in the intestinal mucosa and in the 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 Marita® and lead to undesirable effects, such as changes in the pattern of menstrual bleeding.

Reduced clearance of sex hormones due to enzyme inhibition may enhance the therapeutic effect of Marita® 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 occur after several days of therapy. Maximum enzyme induction is generally observed after several weeks.

Enzyme induction may persist for up to 4 weeks after discontinuation of therapy.

The effect of the CYP3A4 inducer rifampicin was studied in healthy postmenopausal women. Concomitant administration of rifampicin with an oral formulation of estradiol valerate/dienogest resulted in a significant reduction in the steady-state concentration and systemic exposure of dienogest and estradiol. 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 combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors in combination with hepatitis C virus inhibitor combinations may increase or decrease plasma levels of progestin. The combined 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 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 dienogest on other medicinal products

Based on in vitro inhibition studies, clinically relevant interactions of dienogest with other drugs whose metabolism is mediated by cytochrome P450 enzymes are unlikely.

Interaction with food

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

Laboratory tests

The use of progestogens may influence the results of certain laboratory tests, particularly biochemical parameters of liver, thyroid and kidney function, adrenal 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 Marita® is a progestogen-only preparation, it is considered that special precautions and safety measures related to the use of progestin-containing drugs also apply to dienogest, although not all warnings and preventive measures are based on appropriate clinical trial results specifically for this drug.

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

Severe uterine bleeding

Uterine bleeding, for example in women with adenomyosis or uterine fibroids, may be exacerbated by the use of Marita®. If bleeding is pronounced and does not stop over a prolonged 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 pattern of menstrual bleeding in most women (see section "Adverse reactions").

Circulatory disorders

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

Some studies suggest a certain, though not statistically significant, increased risk of venous thromboembolism (deep vein thrombosis, pulmonary embolism) associated with the use of progestogen-only preparations. Well-established factors increasing the risk of 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 case of prolonged immobilization, Marita® should be discontinued (at least 4 weeks before elective surgery) and not restarted until at least 2 weeks after full recovery.

The increased risk of thromboembolism in the postpartum period should also be taken into account.

If symptoms of venous or arterial thrombotic diseases 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 estrogen-progestogen combinations. 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 regarding progestogen-only preparations is based on a much smaller number of users, making it 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 OCs.

In rare cases, benign and even more rarely malignant liver tumors have been observed in women using hormonal substances similar to the one contained in Marita®, with some cases leading to life-threatening intra-abdominal bleeding. In case of severe epigastric pain, liver enlargement, or signs of intra-abdominal bleeding, the possibility of a liver tumor should be considered in women taking Marita® during differential diagnosis.

Osteoporosis

Changes in bone mineral density (BMD).

Use of dienogest in adolescents (12–18 years) during a 12-month treatment period was associated with a 1.2% decrease in mean BMD at the lumbar spine (L2–L4). After treatment cessation, BMD increased again in these patients.

The mean relative change in BMD from baseline to end of treatment was −1.2%, with a range between −6% and 5% (95% CI: −1.70% to −0.78%, n=103). Repeat measurements 6 months after treatment completion in a subgroup with reduced BMD values showed a trend toward recovery (mean relative change from baseline: −2.3% at end of treatment and −0.6% at 6 months post-treatment, range between −9% and 6%; 95% CI: −1.20% to 0.06%, n=60).

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

Before initiating treatment, physicians should weigh the benefits of Marita® 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 ages.

No decrease in BMD was observed in adults (see section "Pharmacological properties").

In patients at increased risk of osteoporosis, a careful risk/benefit assessment should be performed before initiating treatment with Marita®, 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 generally does not affect blood pressure in normotensive women. However, if clinically significant, persistent hypertension develops during treatment, Marita® should be discontinued and hypertension treated.

Treatment with Marita® should be discontinued if cholestatic jaundice and/or pruritus, which occurred during pregnancy or previous use of sex hormones, recurs.

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 carefully monitored during treatment with Marita®.

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 Marita®.

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

During treatment with Marita®, 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.

Not used in geriatric practice.

Lactose

One tablet of Marita® contains 62.81 mg of lactose monohydrate. If intolerance to certain sugars is diagnosed, consult a physician before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy

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

Marita® is not recommended for use during pregnancy because there is no need to treat endometriosis during pregnancy.

Breastfeeding period

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

Fertility

Based on available data, ovulation is inhibited in most patients during treatment with dienogest. However, Marita® 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 stopping dienogest treatment.

Ability to influence reaction speed when driving or operating machinery.

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

Dosage and Administration

Administration

For oral use.

Dosage

Take 1 tablet daily without interruption at approximately 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, begin taking tablets from the next pack without any break in treatment.

There is no experience with treating patients with endometriosis using dienogest for longer than 15 months.

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

Any hormonal contraceptives should be discontinued prior to starting therapy with Marita®. If contraception is needed, an additional non-hormonal method of contraception (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 Marita® may be reduced. If one or more tablets are missed, take 1 tablet as soon as the patient remembers, and take the next tablet at the usual time. Similarly, a tablet that was not absorbed due to vomiting or diarrhea should be replaced with another tablet.

Additional information on use in special patient populations

Elderly patients

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

Hepatic impairment

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

Renal impairment

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

Children

Marita® 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 "Pharmacological properties" and "Special instructions for use").

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 lumbar spine BMD of 1.2%. After discontinuation of treatment, BMD increased again in these patients.

Changes in BMD are of particular importance during adolescence and early stages of sexual maturation, which represent a critical period 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 Marita® treatment against the potential risks for each individual adolescent patient (see sections "Pharmacological properties" and "Special instructions for use").

Overdose

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

Adverse reactions

Adverse reactions are listed according to the Medical Dictionary for Regulatory Activities (MedDRA).

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

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

In addition, dienogest treatment 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).

The table below lists adverse reactions according to MedDRA System Organ Classes (SOCs) reported during treatment with dienogest, along with their frequency.

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

Decrease in BMD

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

Reporting suspected adverse reactions

Reporting suspected adverse reactions after authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions.

Shelf life. 3 years.

Do not use the medicinal product after the expiry date stated on the packaging.

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

Keep out of the reach of children.

Packaging.

28 tablets in a blister. 1 blister in a carton.

Prescription status. Prescription only.

Manufacturer. Síndea Pharma, S.L./Cyndea Pharma, S.L.

Manufacturer's address.

Poligono Industrial Emiliano Revilla Sanz, Avda. de Agreda, 31, Olvega, 42110 (Soria), Spain.

Marketing Authorization Holder. JSC "Farmak".

Address of the Marketing Authorization Holder. 63, Kyrylivska St., Kyiv, Ukraine, 04080.