Didromens^® (Tablets) Instructions for Use

Marketing Authorization Holder

Binnopharm Group LLC (Russia)

Manufactured By

Emcure Pharmaceuticals, Ltd. (India)

Contact Information

BINNOPHARM GROUP LLC (Russia)

ATC Code

G03DB01 (Dydrogesterone)

Active Substance

Dydrogesterone (Rec.INN registered by WHO)

Dosage Form

Didromens®

Film-coated tablets, 10 mg: 20 or 28 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, biconvex, with a score on one side and smooth on the other. The cross-section of the tablets reveals a core of white or almost white color, surrounded by one layer of coating. The break line (score) is intended only for breaking to facilitate swallowing and not for dividing into equal doses.

Excipients: tablet core lactose monohydrate, corn starch, hypromellose, colloidal silicon dioxide, magnesium stearate; tablet coating Opadry white Y-1-7000 [hypromellose 2910, titanium dioxide, macrogol (polyethylene glycol)].

10 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs.

Clinical-Pharmacological Group

Gestagen

Pharmacotherapeutic Group

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

Pharmacological Action

Mechanism of action and pharmacodynamic effects

Dydrogesterone is a synthetic progestogen with oral bioavailability, upon administration of which the endometrium transitions into the secretory phase in the uterine mucosa prepared by estrogens. It provides protection against the increased risk of estrogen-induced endometrial hyperplasia and/or cancer. Dydrogesterone does not possess estrogenic, androgenic, anabolic, or glucocorticoid activity.

Dydrogesterone does not suppress ovulation, therefore, pregnancy may occur in women of reproductive age while taking the drug.

In postmenopausal women with an intact uterus, estrogen replacement therapy increases the risk of endometrial hyperplasia and cancer. The addition of a progestogen prevents this additional risk.

Clinical efficacy and safety

Within the framework of randomized clinical studies (LOTUS I and LOTUS II) comparing the efficacy, safety, and tolerability of the oral form of dydrogesterone and the vaginal form of micronized progesterone for luteal phase support in in vitro fertilization cycles, the following was confirmed: in the studied patient population, the pregnancy rate at the 12th week of gestation (10th week of pregnancy) was 37.6% and 33.1% (LOTUS I), and 36.7% and 34.7% (LOTUS II) for oral dydrogesterone and vaginal micronized progesterone, respectively. The difference in pregnancy rates between the two groups was 4.7 (95% CI, -1.2; 10.6) (LOTUS I) and 2.0 (95% CI, -4.0; 8.0) (LOTUS II).

In the safety evaluation sample, which included 1029 patients (LOTUS I) and 1030 patients (LOTUS II) who received at least one dose of the study drug, the incidence of the most frequent adverse reactions was comparable in both treatment groups. Due to the nature of the studied patient population/indication, a certain number of abortions/miscarriages in the early stages, especially before the 12th week of gestation (10th week of pregnancy), is expected, as the expected pregnancy rate at this time point is approximately 35%.

The safety profile observed in both LOTUS studies is consistent with expectations, taking into account the well-studied safety profile of dydrogesterone and the patient population/indication.

Pharmacokinetics

Absorption

After oral administration, Dydrogesterone is rapidly absorbed. The C_max of dydrogesterone and its active metabolite DHD is about 3.2 ng/ml and 57 ng/ml, reached within 0.5 and 1.5 hours after administration, respectively. The AUC is about 9.1 and 220 ng×h/ml, respectively.

When a single dose of dydrogesterone is taken simultaneously with food, the achievement of C_max of dydrogesterone in plasma is delayed by approximately 1 hour, leading to a decrease in C_max by approximately 20%, without affecting the extent of exposure to dydrogesterone and DHD.

The observed effect of simultaneous food intake on the C_max of dydrogesterone is considered clinically insignificant, so the drug can be taken regardless of meals.

Distribution

After oral administration of dydrogesterone, the apparent V_d is approximately 1400 L. More than 90% of dydrogesterone and DHD binds to plasma proteins.

Metabolism

After oral administration, Dydrogesterone is rapidly metabolized to DHD. The main metabolic pathway, resulting in the formation of the main pharmacologically active metabolite DHD, occurs in the cytosol of human cells catalyzed by aldo-keto reductase 1C (AKR 1C). In addition, there is another metabolic pathway involving cytochrome P450 (CYP) isoenzymes, predominantly CYP3A4, with the formation of several less important metabolites. The concentrations of the main active metabolite DHD reach peak values at the same time as dydrogesterone. The plasma concentration of DHD is significantly higher than that of dydrogesterone. The ratios of AUC and C_max of DHD to dydrogesterone are approximately 25 and 20, respectively. The mean terminal half-life for both dydrogesterone and DHD is about 15 hours. A common property of all metabolites is the preservation of the 4,6-diene-3-one configuration of the parent compound and the absence of a 17α-hydroxylation reaction. This explains the absence of estrogenic and androgenic effects of dydrogesterone.

Excretion

After oral administration of labeled dydrogesterone, an average of 63% of the dose is excreted through the kidneys. The total plasma clearance is 6.4 L/min. Dydrogesterone is completely eliminated from the body within 72 hours. DHD is detected in the urine mainly as glucuronic acid conjugates.

Linearity (non-linearity)

Dydrogesterone exhibits linear pharmacokinetics after single and multiple oral administration in the dose range from 2.5 mg to 10 mg.

When comparing pharmacokinetic parameters after single and multiple administration, it was found that the pharmacokinetics of dydrogesterone and DHD do not change as a result of multiple applications. Css is reached 3 days after the start of treatment.

Indications

For adult women aged 18 years and older with

conditions characterized by progesterone deficiency

• Endometriosis;
• Infertility due to luteal phase insufficiency;
• Threatened miscarriage;
• Habitual miscarriage;
• Premenstrual syndrome;
• Dysmenorrhea;
• Irregular menstruation;
• Secondary amenorrhea;
• Dysfunctional uterine bleeding;
• Luteal phase support during assisted reproductive technologies (ART);

menopausal hormone therapy (MHT)

• To neutralize the proliferative effect of estrogens on the endometrium as part of MHT in women with disorders due to natural or surgical menopause with an intact (preserved) uterus.

ICD codes

Dosage Regimen

The drug is taken orally. The duration of therapy and doses may be adjusted based on the individual clinical response of the patient and the severity of the pathology within the dosage regimen of the drug presented below.

Missed dose

If a dose is missed, the patient should take the tablet as soon as possible within 12 hours of the usual intake time. If more than 12 hours have passed, the missed tablet should not be taken, and the patient should take the next tablet at the usual time the next day. Missing a dose may increase the likelihood of breakthrough bleeding or spotting.

Children

The safety and efficacy of dydrogesterone in adolescent girls aged 12 to 18 years have not been established.

Adverse Reactions

Summary of the safety profile

In clinical studies in patients receiving dydrogesterone therapy for indications not requiring estrogen administration, the most frequently encountered adverse reactions were: headache/migraine, nausea, vomiting, abdominal pain, menstrual cycle disorder, breast tenderness/pain, vaginal bleeding.

Tabulated summary of adverse reactions

In clinical studies using dydrogesterone (n=3483) for indications not requiring estrogen administration, in 2 interventional studies of dydrogesterone use for luteal phase support during ART (n=1036), as well as during post-registration use (spontaneous reports), adverse reactions with the following frequencies of occurrence were observed: very common (≥1/10), common (≥1/100 but <1/10), uncommon (≥1/1000 but <1/100), rare (≥1/10000 but <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from the available data).

Description of adverse reactions is presented in the following table

* Adverse reactions that were described in spontaneous reports but were not recorded in clinical studies were classified as rare adverse reactions based on the fact that the upper limit of the 95% confidence interval of their frequency did not exceed 3/x, where x=3483 (total number of participants in clinical studies).

When using some progestogens in combination with estrogens as part of MHT, the following adverse reactions have been noted

• Breast cancer, endometrial hyperplasia, endometrial cancer, ovarian cancer;
• VTE;
• Myocardial infarction, coronary heart disease, ischemic stroke.

Reporting of suspected adverse reactions

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

Contraindications

• Hypersensitivity to dydrogesterone and/or to any of the excipients included in the drug;
• Diagnosed or suspected malignant hormone-dependent neoplasms caused by sex hormones (including meningioma);
• Vaginal bleeding of unknown etiology;
• Impaired liver function due to acute or chronic liver diseases currently or in history (until normalization of liver function tests);
• Malignant liver tumors currently or in history;
• Breastfeeding period;
• Porphyria currently or in history;
• Age under 18 years due to lack of data on efficacy and safety in adolescent girls under 18 years;
• Spontaneous abortion (miscarriage) or missed abortion during luteal phase support as part of ART.

When combined with estrogens

When used for the indication of menopausal hormone therapy (MHT)

• Untreated endometrial hyperplasia;
• Arterial and venous thrombosis, thromboembolism currently or in history (including deep vein thrombosis, pulmonary embolism, myocardial infarction, thrombophlebitis, cerebrovascular accidents of hemorrhagic and ischemic type);
• Identified predisposition to venous or arterial thrombosis (activated protein C resistance, hyperhomocysteinemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant)).

With caution

• Depression currently or in history;
• Conditions that previously appeared or worsened during a previous pregnancy or previous intake of sex hormones, such as: cholestatic jaundice, herpes during pregnancy, severe skin itching, otosclerosis.

When using dydrogesterone in combination with estrogens, caution should be exercised in the presence of risk factors for the development of thromboembolic conditions, such as angina pectoris, prolonged immobilization, severe forms of obesity (body mass index over 30 kg/m²), old age, extensive surgical interventions, systemic lupus erythematosus, cancer; in patients receiving anticoagulant therapy; in the presence of endometriosis, uterine fibroids; history of endometrial hyperplasia; liver adenoma; diabetes mellitus with or without vascular complications; arterial hypertension; bronchial asthma; epilepsy; migraine or severe headache in history; cholelithiasis; chronic renal failure; in the presence of a history of risk factors for the development of estrogen-dependent tumors (for example, first-degree relatives with breast cancer).

Use in Pregnancy and Lactation

Pregnancy

More than 9 million pregnant women have taken Dydrogesterone. To date, there are no data on the negative effects of dydrogesterone when used during pregnancy.

The drug can be used during pregnancy (see the “Indications” section).

There are isolated reports of a possible association of the risk of hypospadias with the use of some progestogens. However, the many different factors influencing pregnancy do not allow an unambiguous conclusion to be made about the effect of progestogens on the risk of hypospadias. The results of clinical studies in which a limited number of women received Dydrogesterone in early pregnancy did not confirm an increased risk of hypospadias. Currently, there are no other epidemiological data.

Breastfeeding period

There are no data regarding the penetration of dydrogesterone into breast milk. When using other progestogens, it has been established that progestogens and their metabolites penetrate into breast milk in small quantities. The existence of a risk to the child has not been studied, therefore the use of the drug during breastfeeding is contraindicated.

Use in Hepatic Impairment

The use of the drug is contraindicated in cases of impaired liver function due to acute or chronic liver diseases currently or in the anamnesis (until liver function tests normalize); malignant liver tumors currently or in the anamnesis.

Use in Renal Impairment

Caution should be exercised when using dydrogesterone in combination with estrogens in patients with chronic renal failure.

Pediatric Use

The use of the drug is contraindicated under the age of 18 years (due to the lack of data on efficacy and safety in adolescent girls under 18 years of age).

Geriatric Use

Caution should be exercised when using dydrogesterone in combination with estrogens in elderly patients.

Special Precautions

Before starting therapy with dydrogesterone for dysfunctional uterine bleeding, an organic cause of bleeding must be excluded. With long-term use of the drug, periodic examinations by a gynecologist are recommended, the frequency of which is determined individually, but not less than once every six months. In the first months of treatment for abnormal uterine bleeding, breakthrough bleeding or spotting may occur. If breakthrough bleeding or spotting occurs after a certain period of taking the drug or continues after a course of treatment, you should consult your doctor and conduct an appropriate additional examination, if necessary, perform an endometrial biopsy to exclude neoplasms in the endometrium.

When prescribing dydrogesterone in combination with estrogens for the purpose of MHT, you should carefully read the contraindications and special instructions related to the use of estrogens.

MHT should be prescribed for the treatment of menopausal symptoms that adversely affect the patient’s quality of life. The benefit/risk ratio of the ongoing MHT should be assessed annually. Therapy should be continued as long as the potential benefit outweighs the potential risk.

There is limited data on the risks associated with MHT in the treatment of premature menopause. Due to the low absolute risk in young women, the benefit/risk ratio for them may be more favorable compared to that in older women.

If one of the following disorders occurs for the first time or worsens during the use of the drug, the issue of discontinuing treatment should be considered

• Exceptionally severe headache, migraine or symptoms that may indicate cerebral ischemia;
• Significant increase in blood pressure;
• Occurrence of venous thromboembolism (VTE).

In cases of threatened or habitual miscarriage, fetal viability should be assessed, and during treatment it is necessary to monitor whether the pregnancy continues to develop and whether the embryo is alive.

Conditions requiring observation

The following rare conditions are known to be susceptible to the influence of sex hormones and may occur or worsen during pregnancy or during the use of sex hormones

• Cholestatic jaundice;
• Herpes of pregnancy;
• Severe itching;
• Otosclerosis;
• Porphyria.

Patients with a history of depression should be closely monitored: if severe depression recurs, treatment with dydrogesterone should be discontinued.

Medical examination

Before starting the use of a combination of dydrogesterone and estrogen (for MHT), a complete individual and family history should be collected. An objective examination (including examination of the pelvic organs and mammary glands) should be carried out to identify possible contraindications and conditions requiring precautions.

During treatment, it is recommended to periodically monitor individual tolerance to MHT. The patient should be informed about what changes in the mammary glands she should report to the doctor (see the subsection “Breast cancer”). Studies, including mammography, should be carried out in accordance with generally accepted screening, taking into account individual characteristics and the clinical picture.

Endometrial hyperplasia and cancer

In women with an intact uterus, the risk of endometrial hyperplasia and cancer increases with long-term estrogen monotherapy. Depending on the duration and dose of estrogen, the risk may be 2-12 times higher than in women not using estrogen drugs. After stopping estrogen treatment, this risk persists for at least 10 years.

Cyclic use of progestogens, including dydrogesterone (for at least 12 days of a 28-day cycle) or the use of a sequential combined MHT regimen in women with a preserved uterus can prevent the increased risk of endometrial hyperplasia and cancer with estrogen monotherapy.

In the first months of treatment for abnormal uterine bleeding, breakthrough bleeding or spotting may occur. If breakthrough bleeding or spotting occurs after a certain period of taking the drug or continues after a course of treatment, you should consult your doctor and conduct an appropriate additional examination, if necessary, perform an endometrial biopsy to exclude neoplasms in the endometrium.

Breast cancer

Available data indicate that the risk of breast cancer increases in women who received MHT with combined estrogen and progestogen drugs, or with estrogen monotherapy. The level of risk depends on the duration of MHT.

Concomitant use with estrogens and progestogens results of a meta-analysis of prospective epidemiological studies and the WHI study (Women’s Health Initiative study) confirm an increased risk of developing breast cancer in women taking drugs containing a combination of estrogen and progesterone as part of MHT. The risk increases after approximately 3 years (from 1 to 4 years) of therapy. The results of an extensive meta-analysis showed that after stopping treatment, the excess risk will decrease over time, and the time required to return to the baseline level depends on the duration of previous MHT use. If MHT drugs were taken for more than 5 years, the risk may persist for 10 years or more. While taking MHT drugs, especially with combined therapy with estrogens and progestogens, an increase in breast tissue density may be observed during mammography, which may complicate the diagnosis of breast cancer.

Ovarian cancer

Ovarian cancer is significantly less common than breast cancer. Epidemiological data obtained from a large-scale meta-analysis indicate a slight increase in risk for women receiving MHT in the form of estrogen monotherapy or combined therapy with estrogens and progestogens. The increase in this risk becomes apparent with therapy lasting more than 5 years, and after its cessation, the risk gradually decreases over time. The results of a number of other studies, including WHI, indicate that combined MHT is associated with a similar or slightly lower risk of developing ovarian cancer (see the “Adverse Reactions” section).

Venous thromboembolism (VTE)

MHT is associated with a 1.3-3-fold increase in the risk of developing VTE, i.e., deep vein thrombosis or pulmonary embolism. The likelihood is highest in the first year of MHT than in subsequent years. Patients with diagnosed thrombophilia have an increased risk of developing VTE, and MHT may increase this risk. For this reason, MHT is contraindicated in such patients.

Risk factors for VTE include taking estrogens, old age, undergoing extensive surgery, prolonged immobilization, obesity (BMI >30 kg/m²), pregnancy, postpartum period, systemic lupus erythematosus and cancer. There is no clear data on the possible role of varicose veins in the development of VTE.

If prolonged immobilization is necessary after surgical interventions, MHT drugs should be discontinued 4-6 weeks before surgery; resumption of the drug is possible after the woman has fully restored motor activity.

Women with no history of VTE, but with a family history of thrombosis at a young age in first-degree relatives, after detailed counseling about possible limitations and disadvantages of therapy, may be offered screening (only some hereditary defects of the hemostatic system are detected during screening).

If thrombophilia associated with thrombosis is detected in family members or in the case of a severe defect (for example, antithrombin III deficiency, protein C, protein S or a combination of defects), MHT is contraindicated.

If the patient is taking anticoagulants, the benefit/risk of prescribing MHT should be carefully assessed. MHT drugs are not prescribed until a thorough assessment of possible risk factors for thromboembolism is completed or anticoagulant therapy is started. If thrombosis develops after starting therapy, MHT should be discontinued.

You should urgently consult a doctor if any symptoms appear that indicate possible thromboembolism (painful swelling of the lower extremities, sudden chest pain, shortness of breath, visual impairment).

Coronary heart disease (CHD)

Data from randomized controlled trials indicate no protective effect on the development of myocardial infarction in women with or without CHD receiving MHT in the form of combined therapy with estrogens and progestogens or estrogen monotherapy.

Concomitant use with estrogens and progestogens:the relative risk of developing CHD increases slightly during combined MHT. The absolute risk of developing CHD depends on age. The number of cases of CHD associated with the use of MHT in healthy women of an age close to the onset of natural menopause is very low, but the risk increases with age.

Ischemic stroke

Combined therapy with estrogens and progestogens or estrogens alone is associated with a 1.5-fold increase in the risk of ischemic stroke. The relative risk does not change with age and does not depend on the time of menopause. However, the incidence of stroke depends on age, and the overall risk of stroke in women receiving MHT will increase with age.

Excipients

The drug contains lactose.

Patients with rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this drug.

Effect on the ability to drive vehicles and mechanisms

Dydrogesterone has a slight effect on the ability to drive vehicles and mechanisms.

Caution should be exercised when driving vehicles and mechanisms, taking into account the possibility of adverse reactions from the nervous system (mild drowsiness and/or dizziness, especially in the first hours of administration).

Overdose

Data on cases of drug overdose are limited. Dydrogesterone was well tolerated after oral administration (the maximum described daily dose was 360 mg).

Symptoms nausea, vomiting, dizziness and drowsiness are possible.

Treatment there is no specific antidote, treatment should be symptomatic.

Drug Interactions

According to in vitro data, the main active metabolite 20α-dihydrodydrogesterone (DHD) and to a lesser extent also Dydrogesterone are mainly metabolized by CYP3A4.

Drugs that increase the clearance of progestogens (reduce effectiveness due to enzyme induction), for example: barbiturates, phenytoin, carbamazepine, primidone, rifampicin and anti-HIV drugs such as ritonavir, nevirapine and efavirenz, as well as possibly drugs containing St. John’s wort (Hypericum perforatum).

An increase in the clearance of dydrogesterone can lead to a clinical decrease in effect and a change in the nature of bleeding.

Drugs with varying effects on the clearance of progestogens

Many combinations of human immunodeficiency virus (HIV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with hepatitis C virus (HCV) inhibitors, when taken simultaneously with progestogens, can increase or decrease the concentration of progestogen in the blood plasma. In some cases, the overall effect of these changes may be clinically significant.

For this reason, when taking them simultaneously, you should read the information about HIV/HCV treatment drugs to determine potential interactions and any associated recommendations.

Drugs that reduce the clearance of progestogens (enzyme inhibitors)

The clinical significance of possible interactions with enzyme inhibitors is unknown. Concomitant use of strong CYP3A4 inhibitors may increase plasma concentrations of progestogens.

Storage Conditions

The drug should be stored in the original packaging (blister in a box) in a place protected from light at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life is 2 years.

Dispensing Status

The drug 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.