Duphaston

Duphaston is a drug that contains a synthetic progesterone called dydrogesterone. It is widely used in gynecology for a number of different indications, including the treatment of some forms of luteal phase deficiency, endometriosis, abortion, and other menstrual cycle disorders. Dydrogesterone, like natural progesterone, affects estrogen-dependent processes in the body, making it an important component in regulating hormonal balance in women.

Indications Duphaston

1. Luteal phase insufficiency.
2. Endometriosis.
3. Prevention of threatened miscarriages.
4. Resolution of functional uterine cysts.
5. Combined hormonal therapy in case of short-term therapy against the background of estrogen deficiency.

Release form

Duphaston is usually available in tablet form for oral (internal) use.

Pharmacodynamics

1. Progestogenic action:

   • Effect on the endometrium: Dydrogesterone induces a secretory transformation of the proliferative endometrium, which helps prepare it for possible implantation of the fertilized egg. This action is similar to the physiological effect of endogenous progesterone in the luteal phase of the menstrual cycle.
   • Pregnancy support: Dydrogesterone maintains the endometrium to support pregnancy and prevents miscarriages associated with progesterone deficiency.

2. Antiestrogenic action:

   • Regulation of hormonal balance: Dydrogesterone counteracts endometrial hyperplasia and other hyperplastic changes caused by excess estrogen exposure. This is important in the treatment of conditions associated with hyperestrogenism, such as dysfunctional uterine bleeding and endometriosis.

3. Lack of androgenic activity:

   • Unlike some other synthetic progestogens, dydrogesterone does not have androgenic activity. This means that it does not cause side effects related to the skin, hair and lipid metabolism, such as acne, hirsutism or changes in blood lipid levels.

4. Lack of estrogenic activity:

   • Dydrogesterone does not exhibit estrogenic activity, which reduces the risk of estrogen-related side effects, such as an increased risk of thromboembolism and breast cancer.

5. Lack of glucocorticoid and anabolic activity:

   • Dydrogesterone does not affect glucose metabolism and does not cause anabolic effects, which makes it safe for patients with glucose metabolism and metabolic disorders.

Clinical effects:

• Regulation of the menstrual cycle: Dydrogesterone is effectively used to normalize the menstrual cycle in cases of dysfunctional uterine bleeding and secondary amenorrhea.
• Treatment of endometriosis: By reducing the proliferative activity of endometrioid tissue and reducing pain.
• Pregnancy support: Used for threatened and habitual miscarriages associated with progesterone deficiency.
• Hormone replacement therapy (HRT): Used as part of HRT to prevent endometrial hyperplasia in menopausal women receiving estrogens.

Pharmacokinetics

Suction:

• Oral absorption: Dydrogesterone is rapidly absorbed from the gastrointestinal tract after oral administration.
• Maximum concentration: The maximum concentration (Cmax) in blood plasma is reached approximately 2 hours after administration of the dose.

Distribution:

• Distribution in the body: Dydrogesterone and its metabolites are widely distributed throughout the body tissues.
• Protein binding: High degree of binding to plasma proteins, which facilitates efficient distribution of the active substance.

Metabolism:

• Hepatic metabolism: Dydrogesterone is extensively metabolized in the liver. The main metabolite is 20α-dihydrodydrogesterone (DHD), which also has progestogenic activity.
• Pharmacologically active metabolites: DHD, the main metabolite, reaches its maximum plasma concentration 1.5 hours after administration of dydrogesterone. The ratio of Cmax of DHD to dydrogesterone is approximately 1.7.

Withdrawal:

• Elimination half-life: The elimination half-life of dydrogesterone is about 5-7 hours, and its metabolite DHD is about 14-17 hours.
• Urinary excretion: Dydrogesterone and its metabolites are excreted primarily in the urine. About 63% of the administered dose is excreted in the urine within 72 hours.
• Complete elimination: Complete elimination of dydrogesterone and its metabolites from the body occurs within approximately 72 hours.

Special instructions:

• Pharmacokinetics in the elderly: There are no specific data on the effect of age on the pharmacokinetics of dydrogesterone, however, given the overall safety profile, dose adjustment in the elderly is generally not required.
• Renal impairment: Dose adjustment is generally not required in mild to moderate renal impairment, but individual patient characteristics should be taken into account.
• Hepatic impairment: Patients with severe hepatic impairment may require special monitoring due to altered drug metabolism.

Dosing and administration

Below are basic recommendations for the method of administration and dosage for various indications.

1. Dysfunctional uterine bleeding

• Acute therapy: 10 mg twice daily for 5-7 days to stop bleeding.
• Prevention: 10 mg twice daily from day 11 to day 25 of the cycle.

2. Secondary amenorrhea

• Combination therapy with estrogens: 10 mg twice daily from day 11 to day 25 of the cycle.

3. Endometriosis

• Dose: 10 mg two to three times a day from day 5 to day 25 of the cycle or continuously.

4. Premenstrual syndrome (PMS)

• Dose: 10 mg twice daily from day 11 to day 25 of the cycle.

5. Dysmenorrhea

• Dose: 10 mg twice daily from day 5 to day 25 of the cycle.

6. Irregular menstruation

• Dose: 10 mg twice daily from day 11 to day 25 of the cycle.

7. Threatened miscarriage

• Initial dose: 40 mg once, then 10 mg every 8 hours until symptoms disappear.

8. Habitual miscarriage

• Dose: 10 mg twice daily until the 20th week of pregnancy, then gradually reduce the dose.

9. Hormone replacement therapy (HRT)

• In combination with estrogens in cyclic or sequential therapy: 10 mg once daily during the last 12-14 days of each 28-day cycle.

10. Luteal insufficiency, including infertility

• Dose: 10 mg twice daily from day 14 to day 25 of the cycle, continue treatment continuously for at least 6 cycles, as well as during the first months of pregnancy.

General recommendations:

• Application: Tablets should be taken orally with a sufficient amount of water. Can be taken regardless of meals.
• Missed dose: If you miss a dose, take it as soon as possible. If it is almost time for your next dose, do not double the dose, just continue taking it as usual.
• Stopping use: It is not recommended to stop taking the drug abruptly without consulting a doctor, especially if the drug is being used to maintain pregnancy or in HRT.

Important notes:

• Treatment monitoring: Regular consultations with your doctor are necessary to assess the effectiveness and safety of your therapy.
• Testing and monitoring: In some cases, monitoring of hormone levels and the condition of the endometrium may be necessary.

Use Duphaston during pregnancy

1. Use in threatened miscarriage: A systematic review found that dydrogesterone significantly reduced the risk of miscarriage in women with threatened miscarriage. In a study of 660 women, dydrogesterone reduced the miscarriage rate from 24% to 13% compared with the control group (Carp, 2012).
2. Use in recurrent miscarriage: Another systematic review including data on 509 women found that dydrogesterone reduced the rate of recurrent miscarriage from 23.5% to 10.5% compared to the control group. This supports the effectiveness of dydrogesterone in reducing the risk of miscarriage in women with a history of recurrent miscarriage (Carp, 2015).
3. Luteal phase support: A study comparing oral dydrogesterone with vaginal progesterone for luteal phase support in in vitro fertilization (IVF) found that both drugs were similarly effective in increasing the chance of pregnancy. However, dydrogesterone was better tolerated and caused fewer side effects (Tomić et al., 2015).
4. Modulation of the immune response: Dydrogesterone may positively influence the immune response in women with recurrent miscarriages. Studies show that dydrogesterone treatment is associated with an increase in progesterone-blocking factors and a shift from Th1 to Th2 cytokines, which promotes successful pregnancy (Walch et al., 2005).
5. Prevention of risks after amniocentesis: The study showed that the use of dydrogesterone reduces the risk of complications after amniocentesis, such as leakage of amniotic fluid and uterine contractions, compared with the control group (Korczyński, 2000).

Contraindications

1. Transfer of previously developed allergic reactions to dydrogesterone or other components of the drug.
2. Thrombosis and thromboembolic disorders (including history).
3. Liver problems such as acute or chronic hepatitis, severe liver dysfunction.
4. If you have or are predisposed to developing hormone-sensitive tumors, such as breast cancer or cancer of estrogen-dependent organs.
5. Uncontrolled arterial hypertension.
6. Prolactin-dependent tumors (eg, pituitary prolactinoma).
7. Impaired renal or cardiovascular function.
8. Congenital or acquired angioedema.
9. Severe diabetes mellitus, true or diabetic migraine, as well as obvious early signs of venous or arterial thrombosis (eg, thrombophlebitis, venous thromboembolism syndrome, stroke, myocardial infarction).

Side effects Duphaston

1. Headaches.
2. Dizziness or fatigue.
3. Pain in the mammary glands.
4. Gastrointestinal disturbances such as nausea, vomiting, diarrhea or constipation.
5. Edema (usually soft tissue).
6. Mood changes.
7. Menstrual bleeding or spotting outside of menstrual periods.
8. Weight gain.

Overdose

• Nausea.
• Vomit.
• Dizziness.
• Abdominal pain.
• Drowsiness.
• Vaginal bleeding.

Interactions with other drugs

1. Drugs that affect liver enzymes:

   • Liver enzyme inducers (eg, rifampicin, phenytoin, carbamazepine, barbiturates):
     • These drugs may increase the metabolism of dydrogesterone in the liver, which may reduce its effectiveness.
   • Liver enzyme inhibitors (eg, ketoconazole, erythromycin):
     • These drugs may slow down the metabolism of dydrogesterone, which may increase its concentration in the blood and increase the risk of side effects.

2. Hormonal drugs:

   • Other progestogens and estrogens:
     • When used simultaneously with other hormonal drugs, dydrogesterone may enhance or weaken their effects. It is important to adjust the dosage under the supervision of a doctor.

3. Antibacterial and antifungal agents:

   • Some antibiotics and antifungals may alter the metabolism of dydrogesterone. For example, rifampin (an antibiotic) and griseofulvin (an antifungal) may reduce its effectiveness.

4. Antidepressants and antipsychotics:

   • Some interactions may occur when used concomitantly with antidepressants and antipsychotics, requiring patient monitoring for possible changes in effects and side effects.

5. Anticoagulants:

   • When used concomitantly with anticoagulants (eg, warfarin), careful monitoring of blood coagulation parameters may be required, since dydrogesterone may alter their effectiveness.

6. Antidiabetic drugs:

   • Hormonal drugs may affect glucose metabolism, so dose adjustments of antidiabetic drugs may be required in patients with diabetes mellitus.