Duphaston^® (Tablets) Instructions for Use

Marketing Authorization Holder

Abbott Healthcare Products, B.V. (Netherlands)

Manufactured By

Abbott Biologicals, B.V. (Netherlands)

Or

Veropharm, JSC (Russia)

Packaging and Quality Control Release

ABBOTT BIOLOGICALS, B.V. (Netherlands)

Or

VEROPHARM, JSC (Russia)

Contact Information

ABBOTT LABORATORIES LLC (Russia)

ATC Code

G03DB01 (Dydrogesterone)

Active Substance

Dydrogesterone (Rec.INN registered by WHO)

Dosage Form

Duphaston®

Film-coated tablets, 10 mg: 20, 28, or 112 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, round, biconvex, with beveled edges, with a score on one side, with an engraving “155” on both sides of the score; the break line (score) is intended only for breaking to facilitate swallowing, and not for dividing into equal doses.

Excipients: lactose monohydrate – 111.1 mg, hypromellose, corn starch, colloidal silicon dioxide, magnesium stearate; mixture for white film coating: hypromellose, polyethylene glycol 400, titanium dioxide (E171).

14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (8) – cardboard packs.
20 pcs. – blisters (1) – cardboard packs.

Clinical-Pharmacological Group

Gestagen

Pharmacotherapeutic Group

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

Pharmacological Action

Pharmacodynamics

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, when taking Duphaston^®, pregnancy may occur in women of reproductive age.

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 rate 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 events was comparable in both treatment groups. Due to the nature of the studied patient population/indication, a certain number of early abortions/miscarriages is expected, especially before the 12th week of gestation (10th week of pregnancy), as the expected pregnancy rate at this time point is approximately 35%.

The safety profile observed in both LOTUS studies is as expected, 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 in plasma are about 3.2 ng/ml and 57 ng/ml and are reached 0.5 and 1.5 hours after administration, respectively. The AUC is about 9.1 and 220 ng×h/ml, respectively.

After a single dose, food delays the achievement of C_max of dydrogesterone in plasma by about 1 hour, leading to a decrease in C_max of dydrogesterone in plasma by about 20%, without affecting the extent of exposure to dydrogesterone and DHD.

The observed effect of simultaneous food intake on the C_max of dydrogesterone in plasma is considered clinically insignificant. Therefore, Duphaston^® can be taken regardless of meals.

Distribution

After oral administration of dydrogesterone, the apparent V_d is about 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 (AKR1C). In addition, there is another metabolic pathway involving cytochrome P450 (CYP) isoenzymes, mainly CYP3A4, forming several less important metabolites. The concentrations of the main active metabolite DHD reach peak values at the same time as dydrogesterone. The concentration of DHD in plasma 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 T_1/2 of final elimination 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 in dydrogesterone.

Excretion

After oral administration of labeled dydrogesterone, an average of 63% of the dose is excreted through the kidneys (in urine). The total plasma clearance is 6.4 L/min. Dydrogesterone is completely eliminated from the body within 72 hours. DHD is detected in 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 oral administration, it was found that the pharmacokinetics of dydrogesterone and DHD do not change as a result of multiple use. Steady-state concentration is reached 3 days after the start of treatment.

Indications

Conditions characterized by progesterone deficiency

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

Hormone replacement therapy (HRT)

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

ICD codes

Dosage Regimen

The drug is taken orally.

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

Endometriosis 10 mg 2-3 times/day from the 5th to the 25th day of the menstrual cycle or continuously. It is recommended to start with the maximum dose.

Infertility (due to luteal phase insufficiency) 10 mg/day from the 14th to the 25th day of the cycle. Treatment should be carried out continuously for at least six consecutive cycles. In the first months of pregnancy, it is recommended to continue treatment according to the scheme described for habitual abortion.

Threatened abortion 40 mg once, then 10 mg every 8 hours until symptoms disappear.

Habitual abortion 10 mg 2 times/day until the 20th week of pregnancy, followed by a gradual dose reduction.

Premenstrual syndrome 10 mg 2 times/day from the 11th to the 25th day of the menstrual cycle.

Dysmenorrhea 10 mg 2 times/day from the 5th to the 25th day of the menstrual cycle.

Irregular menstruation 10 mg 2 times/day from the 11th to the 25th day of the menstrual cycle.

Secondary amenorrhea an estrogen drug once/day from the 1st to the 25th day of the cycle together with 10 mg of Duphaston^® 2 times/day from the 11th to the 25th day of the menstrual cycle.

Dysfunctional uterine bleeding (to stop bleeding) 10 mg 2 times/day for 5 or 7 days.

Dysfunctional uterine bleeding (to prevent bleeding) 10 mg 2 times/day from the 11th to the 25th day of the menstrual cycle.

Luteal phase support during ART 10 mg 3 times/day starting from the day of egg retrieval and continuing for 10 weeks (if pregnancy is confirmed). If a dose is missed, the patient should take the tablet as soon as possible and consult a doctor.

HRT in combination with estrogens in a continuous sequential regimen – 10 mg of dydrogesterone daily for 14 consecutive days within a 28-day cycle. In a cyclic therapy regimen (when estrogens are used in 21-day courses with 7-day breaks) – 10 mg of dydrogesterone daily during the last 12-14 days of estrogen intake. If a biopsy or ultrasound indicates an insufficient response to the progestogen drug, the daily dose of dydrogesterone should be increased to 20 mg.

When taking dydrogesterone at a dose of 20 mg/day, the tablets should be distributed throughout the day (morning/evening). Usually, “withdrawal” bleeding occurs during the intake of dydrogesterone. The use of combined HRT should be with the minimum effective dose and for the minimum duration, taking into account the purpose of treatment. The risks of HRT should be assessed individually for each woman and periodically reviewed.

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

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

Adverse Reactions

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

In clinical studies using dydrogesterone (n=3483) for indications not requiring estrogen administration, in two interventional studies of dydrogesterone use for luteal phase support during assisted reproductive technologies (n=1036), as well as during post-marketing use (spontaneous reports), adverse reactions were observed with the following frequencies of occurrence: 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).

The 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 (the total number of participants in clinical studies).

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

• Breast cancer, endometrial hyperplasia, endometrial cancer, ovarian cancer;
• Venous thromboembolism;
• Myocardial infarction, coronary artery disease, ischemic stroke.

Contraindications

• Hypersensitivity to dydrogesterone and/or other components of 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;
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome;
• 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 assisted reproductive technologies (ART).

When combined with estrogens

When used for the indication of hormone replacement therapy (HRT)

• 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 (BMI over 30 kg/m²), old age, extensive surgical interventions, systemic lupus erythematosus, cancer; in patients receiving anticoagulant therapy; with 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; with 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 effect of dydrogesterone when used during pregnancy.

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

There are isolated reports of a possible association between the risk of developing hypospadias and the use of some progestogens. However, the multitude of various factors influencing pregnancy does not allow for a definitive conclusion regarding the influence of progestogens on the risk of hypospadias. Results from clinical studies in which a limited number of women received Dydrogesterone in early pregnancy did not confirm an increased risk of hypospadias. Currently, no other epidemiological data are available.

Breastfeeding period

There are no data regarding the penetration of dydrogesterone into breast milk. With the use of 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 Duphaston^® 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 patient’s medical history (until liver function test results normalize); malignant liver tumors currently or in the patient’s medical history.

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 the bleeding must be ruled out. With prolonged 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 some period of taking the drug or continues after the course of treatment, you should consult your doctor and conduct an appropriate additional examination, including, if necessary, an endometrial biopsy to rule out endometrial neoplasms.

When prescribing dydrogesterone in combination with estrogens for HRT, one should carefully familiarize themselves with the contraindications and special instructions associated with the use of estrogens.

HRT 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 HRT 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 HRT for 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, discontinuation of 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 monitoring

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

• Cholestatic jaundice;
• Herpes gestationis;
• Severe itching;
• Otosclerosis;
• Porphyria.

Patients with a history of depression should be under close observation: if severe depression recurs, treatment with dydrogesterone should be discontinued.

Medical examination

Before starting the use of a combination of dydrogesterone and estrogen (for HRT), a complete individual and family medical history should be collected. An objective examination (including pelvic and breast examination) should be performed to identify possible contraindications and conditions requiring precautionary measures.

During treatment, periodic monitoring of individual tolerance to HRT is recommended. The patient should be informed about which changes in the breasts she should report to the doctor. (see “Breast cancer”). Examinations, including mammography, should be performed in accordance with accepted screening practices, 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 discontinuation of 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 HRT regimen in women with a preserved uterus can prevent the increased risk of endometrial hyperplasia and cancer associated 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 some period of taking the drug or continues after the course of treatment, you should consult your doctor and conduct an appropriate additional examination, including, if necessary, an endometrial biopsy to rule out endometrial neoplasms.

Breast cancer

Available data indicate that the risk of breast cancer is increased in women receiving HRT with combined estrogen and progestogen drugs. The level of risk depends on the duration of HRT.

Concomitant use with estrogens and progestogens: results from a meta-analysis of prospective epidemiological studies and the WHI study (Women’s Health Initiative study) confirm an increased risk of breast cancer in women taking medications containing a combination of estrogen and progesterone as part of HRT. The risk increases after approximately 3 years (from one to four years) of therapy. Results from an extensive meta-analysis showed that after discontinuation of treatment, the excess risk will decrease over time, and the time required to return to the baseline level depends on the duration of prior HRT use. If HRT drugs were taken for more than 5 years, the risk may persist for 10 years or more. While taking HRT drugs, especially with combined estrogen and progestogen therapy, 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 from a large-scale meta-analysis indicate a slight increase in risk for women receiving HRT as estrogen monotherapy or combined estrogen and progestogen therapy. The increase in this risk becomes apparent with therapy lasting more than 5 years, and after its discontinuation, the risk gradually decreases over time. Results from a number of other studies, including WHI, indicate that combined HRT is associated with a similar or slightly lower risk of ovarian cancer (see the “Adverse Reactions” section).

Venous thromboembolism

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

Risk factors for venous thromboembolism include estrogen use, advanced age, major surgery, prolonged immobilization, obesity (BMI >30 kg/m²), pregnancy, postpartum period, systemic lupus erythematosus, and cancer. There are no definitive data on the possible role of varicose veins in the development of venous thromboembolism.

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

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

If thrombophilia associated with thrombosis is identified in family members or in the case of a severe defect (e.g., antithrombin III deficiency, protein C deficiency, protein S deficiency, or a combination of defects), HRT is contraindicated.

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

It is necessary to urgently consult a doctor if any symptoms appear that may indicate possible thromboembolism (tenderness or swelling of the lower extremities, sudden chest pain, shortness of breath, visual disturbance).

Coronary heart disease (CHD)

Data from randomized controlled trials indicate no protective effect regarding the development of myocardial infarction in women with or without CHD receiving HRT as combined estrogen and progestogen therapy or estrogen monotherapy.

Concomitant use with estrogens and progestogens the relative risk of developing CHD is slightly increased during combined HRT. The absolute risk of CHD depends on age. The number of CHD cases associated with the use of HRT in healthy women close to the age 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 onset. However, the incidence of stroke depends on age, and the overall risk of stroke in women receiving HRT will increase with age.

Excipients

The drug contains lactose monohydrate. Patients with rare hereditary diseases such as lactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take the drug.

Effect on ability to drive vehicles and machinery

Dydrogesterone has a minor influence on the ability to drive and use machines. Caution should be exercised when driving vehicles and operating machinery, considering the possibility of adverse reactions from the nervous system (mild drowsiness and/or dizziness, especially in the first hours after 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 clinical manifestations of drug overdose are theoretically possible – nausea, vomiting, dizziness, and drowsiness.

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, Dydrogesterone itself are primarily metabolized by CYP3A4.

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

Increased clearance of dydrogesterone may lead to a clinical reduction in effect and a change in the bleeding pattern.

Drugs with varying effects on progestogen clearance

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

For this reason, when taken concomitantly, the information for the HIV/HCV treatment drugs should be consulted to determine potential interactions and any associated recommendations.

Drugs that decrease 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 the plasma concentrations of progestogens.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 5 years. Do not use after the expiration date.

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.