Debra

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEBORA (Debora)

Composition:

Active substances: ethinylestradiol, cyproterone acetate;

1 coated tablet contains ethinylestradiol 0.035 mg, cyproterone acetate 2 mg;

Excipients: lactose monohydrate; corn starch; colloidal anhydrous silicon dioxide; brilliant blue lake (E 133); povidone K 30; talc; magnesium stearate; hypromellose; polyethylene glycol 6000; titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: blue, round, biconvex, film-coated tablets with a break line on one side and smooth on the other side.

Pharmacotherapeutic group. Sex hormones and drugs used in disorders of the reproductive system. Antiandrogens and estrogens. ATC code G03H B01.

Pharmacological properties.

Pharmacodynamics.

Hair follicles and sebaceous glands are sensitive to the action of androgens. The development of acne and seborrhea is caused, in particular, by impaired function of sebaceous glands, which develops due to increased peripheral sensitivity to androgens or elevated androgen levels in blood plasma. Both active ingredients contained in Dianette have a positive therapeutic effect. Cyproterone acetate competitively displaces androgens in the target organ, thereby eliminating androgenic effects. The concentration of androgens in blood plasma subsequently decreases due to the anti-gonadotropic effect. This anti-gonadotropic effect is enhanced by ethinylestradiol, which also stimulates the production of sex hormone-binding globulin (SHBG) in blood plasma. As a result, the level of free, biologically active androgen in blood plasma is reduced. With the use of Dianette (usually after 3–4 months of therapy), acne lesions disappear. Excessive oiliness of hair and skin typically resolves even earlier. Androgen-dependent hair loss also diminishes.

It should be noted that when Dianette is used in women for the treatment of hirsutism, its therapeutic effect develops gradually. Clinically significant results can be expected only after several months of treatment.

Cyproterone acetate is also a potent progestogen that provides contraceptive action when used in combination with ethinylestradi0l. This effect results from the interaction of central and peripheral mechanisms, among which inhibition of ovulation and changes in cervical mucus are considered the most important. In addition, morphological and enzymatic changes in the endometrium create highly unfavorable conditions for implantation.

When used according to instructions, contraceptive protection is effective from the first day of use.

Pharmacokinetics.

Cyproterone acetate

Absorption

After oral administration, cyproterone acetate is completely absorbed over a wide dose range. Its maximum serum concentration is 15 ng/mL, reached approximately 1.6 hours after administration. The absolute bioavailability of cyproterone acetate is about 88%. The relative bioavailability of cyproterone acetate when Dianette is administered is 109% compared to an aqueous microcrystalline suspension.

Distribution

Cyproterone acetate in blood serum is almost entirely protein-bound. Only 3.5–4% of the total steroid concentration remains unbound, while the rest is bound to albumin. Since the binding of cyproterone acetate to SHBG is nonspecific, changes in SHBG levels induced by ethinylestradiol do not affect the pharmacokinetics of cyproterone acetate.

Metabolism

Cyproterone acetate is metabolized via various pathways, including hydroxylation and conjugation. The main metabolite in human plasma is the 15β-hydroxy derivative.

Elimination

The concentration of cyproterone acetate in serum decreases in a biphasic manner, with elimination half-lives of 0.8 hours and 2.3 days, respectively. The plasma clearance rate is approximately 3.6 mL/min⁻¹/kg⁻¹. A portion of the steroid is excreted unchanged in bile. Most of the dose is excreted as metabolites in urine and bile in a ratio of 3:7, with an elimination half-life of 1.9 days. The elimination of metabolites from plasma occurs at a similar rate (elimination half-life of 1.7 days).

Steady state

Accumulation of cyproterone acetate in the body during one treatment cycle is entirely expected, due to its long terminal-phase elimination half-life and daily dosing. Mean maximum serum levels of cyproterone acetate increase from 15 ng/mL (day 1) to 21 ng/mL and 24 ng/mL at the end of the first and third treatment cycles, respectively. Steady-state concentration is reached after approximately 10 days. Due to the long elimination half-life of cyproterone acetate from serum, its accumulation in serum may be observed throughout one treatment cycle, with an accumulation factor of 2–2.5.

Smoking does not affect the pharmacokinetics of cyproterone acetate.

Ethinylestradiol

Absorption

After oral administration, ethinylestradiol is rapidly and completely absorbed. Following a single dose, the maximum serum concentration is approximately 80 pg/mL, reached within 1.7 hours.

When Dianette is administered, the relative bioavailability of ethinylestradiol compared to an aqueous microcrystalline suspension is nearly complete.

Distribution

The apparent volume of distribution for ethinylestradiol is approximately 5 L/kg. Ethinylestradiol binds strongly but nonspecifically to serum albumin. Two percent (2%) of the total amount is present in the unbound form.

The bioavailability of ethinylestradiol may be altered in either direction by other active substances. However, no interaction has been observed with high doses of vitamin C. With continuous use, ethinylestradiol induces hepatic synthesis of SHBG and corticosteroid-binding globulin (CBG). However, the degree of SHBG induction depends on the chemical structure and dose of the accompanying progestogen. During treatment with Dianette, an increase in serum SHBG levels from approximately 100 nmol/L to 300 nmol/L and in serum CBG levels from nearly 50 μg/mL to 95 μg/mL has been observed.

Metabolism

Metabolism of ethinylestradiol occurs during absorption and first-pass liver metabolism, resulting in reduced and variable absolute bioavailability after oral administration. The metabolic clearance rate of ethinylestradiol from plasma has been determined to be approximately 5 mL/min/kg.

In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1, and CYP1A2, and, based on its mechanism of action, also an inhibitor of CYP3A4/5, CYP2C8, and CYP2J2.

Elimination

The serum level of ethinylestradiol decreases in two phases, with elimination half-lives of 1–2 hours and approximately 20 hours, respectively. Due to analytical limitations, these parameters can only be determined for high doses. The substance is not excreted unchanged; ethinylestradiol metabolites are excreted in urine and bile in a ratio of 4:6. The elimination half-life of metabolites is approximately 1 day.

Steady state

Consistent with the terminal-phase elimination half-life of ethinylestradiol in serum and daily intake, steady-state concentrations are reached within 3–4 days and are 30–40% higher than those observed after a single dose.

Clinical characteristics.

Indications.

Treatment of moderate to severe androgen-dependent acne (with or without seborrhea) and/or hirsutism in women of reproductive age.

Deborah should be used only if topical treatments or systemic antibiotic therapy for acne have been ineffective.

Since Deborah is also a hormonal contraceptive, this medication must not be used in combination with other hormonal contraceptives (see section "Contraindications").

Contraindications.

Medicinal products containing combinations of estrogens/progestogens must not be used in the presence of any of the following conditions. If any of these conditions develops for the first time during treatment with such medicinal products, their use must be discontinued immediately.

• Concomitant use of another hormonal contraceptive (see section "Indications")
• Current or past venous thrombotic/thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism).
• Personal or family history of idiopathic venous thromboembolism (VTE) (where family history is based on VTE in parents, siblings, or children at a relatively young age).
• Current or past arterial thrombotic/thromboembolic events (e.g., myocardial infarction), or conditions such as angina pectoris and transient ischemic attack.
• Current or past history of acute cerebrovascular accident.
• Presence of severe or multiple risk factors for venous or arterial thrombosis (see section "Special precautions"), for example:
  • diabetes mellitus with vascular complications,
  • severe arterial hypertension,
  • severe dyslipoproteinemia.
• Inherited or acquired predisposition to venous or arterial thrombosis, including activated protein C resistance (APC), deficiency of antithrombin III, deficiency of protein C, deficiency of protein S, hyperhomocysteinemia, presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).
• History of migraine with focal neurological symptoms.
• Sickle cell anemia.
• Severe liver disease (including biliary disorders such as Dubin-Johnson syndrome and Rotor syndrome), until liver function tests return to normal.
• Current or past history of liver tumors (benign or malignant).
• Vaginal bleeding of unknown etiology.
• Smoking (see section "Special precautions").
• Known or suspected malignant tumors (e.g., of genital organs or breast) dependent on steroid sex hormones.
• Idiopathic jaundice of pregnancy, severe pruritus of pregnancy, herpes gestationis in history, otosclerosis with worsening during previous pregnancies.
• Planned, known, or suspected pregnancy.
• Breastfeeding period.
• Hypersensitivity to the active substances or to any of the excipients of the product.

The medication Deborah must not be used for treatment of men.

The medicinal product Deborah is contraindicated when used concomitantly with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir or sofosbuvir/velpatasvir/voxilaprevir (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Carefully review information on any concurrently administered medicinal product to identify potential interactions.

Effect of other medicinal products on the medicinal product Deborah

Potential interactions may occur with substances that induce microsomal enzyme activity, resulting in increased clearance of sex hormones and occurrence of breakthrough bleeding and/or contraceptive failure.

Enzyme induction may be observed within a few days of treatment initiation. Maximum enzyme induction generally occurs after several weeks. After discontinuation of the inducing agent, enzyme induction may persist for approximately 4 weeks.

Women receiving treatment with any such medicinal products should use an additional barrier method of contraception during this period alongside taking Deborah. The barrier method should be used throughout the duration of treatment with the concomitant medicinal product and for 28 days thereafter. If the period of additional barrier method use is still ongoing when the pack of Deborah tablets is finished, continue taking tablets from the next pack of Deborah without the usual 7-day break.

Substances that increase clearance of the medicinal product Deborah (reduced efficacy of Deborah due to enzyme induction):

e.g., barbiturates, rifampicin, antiepileptic medicinal products (such as barbexaclone, carbamazepine, phenytoin, primidone), and possibly oxcarbazepine, topiramate, felbamate, griseofulvin, and medicinal products containing St. John's wort (Hypericum).

Substances with variable effects on clearance of the medicinal product Deborah

Concomitant use of the medicinal product Deborah with many HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors may lead to increased or decreased plasma concentrations of estrogen or progestogen. In some cases, such changes may be clinically significant.

Active substances that reduce clearance of estrogen-progestogen combinations (enzyme inhibitors)

The clinical significance of potential interactions with enzyme inhibitors remains unclear.

Concomitant use of strong CYP3A4 inhibitors may increase plasma concentrations of estrogens, progestins, or both components.

Etoricoxib at doses of 60 to 120 mg/day has been shown to increase plasma concentrations of ethinylestradiol by 1.4–1.6 times when co-administered with a combined hormonal contraceptive containing 0.035 mg ethinylestradiol.

Effect of estrogen/progestogen combinations on other medicinal products

Estrogen/progestogen combinations, such as the medicinal product Deborah, may affect the metabolism of other medicinal products. Consequently, plasma levels and tissue concentrations may either increase (e.g., cyclosporine) or decrease (e.g., lamotrigine).

The requirement for antidiabetic medicinal products may change due to effects on glucose tolerance.

Clinical data suggest that ethinylestradiol inhibits the clearance of CYP1A2 substrates, leading to mild (e.g., theophylline) or moderate (e.g., tizanidine) increases in their plasma concentrations.

Pharmacodynamic interactions

During clinical trials involving patients receiving treatment for hepatitis C virus (HCV) with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, ALT elevations greater than 5 times the upper limit of normal (ULN) were observed significantly more frequently in women using ethinylestradiol-containing products, such as combined hormonal contraceptives (CHCs). Additionally, in patients treated with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, ALT elevations were observed in women taking ethinylestradiol-containing products such as CHCs (see section "Contraindications").

Therefore, women using the medicinal product Deborah should temporarily switch to an alternative method of contraception (e.g., progestogen-only contraceptives or non-hormonal methods) before starting therapy with the above-mentioned drug combinations. Use of the medicinal product Deborah may be resumed 2 weeks after completion of therapy with the specified combination.

Other forms of interaction

Laboratory tests

Use of medicinal products such as Deborah may affect results of certain laboratory tests. These include biochemical parameters of liver, thyroid, adrenal, and kidney function; plasma levels of binding proteins (e.g., corticosteroid-binding globulin), lipids/lipoprotein fractions, carbohydrate metabolism parameters, and coagulation and fibrinolysis parameters. However, such changes are usually within normal reference ranges.

Deborah must not be used together with an additional hormonal contraceptive; such medicinal products must be discontinued prior to starting treatment with Deborah (see section "Dosage and administration").

Special precautions for use.

Medical examination

Before starting treatment with the medicinal product, a thorough general medical examination is recommended (including measurement of body weight, blood pressure, examination of the cardiovascular system, lower limbs and skin, urine analysis for glucose and acetone, and evaluation of the hepatobiliary system, if necessary), gynecological examination (including breast examination and cytological examination of the cervix (the sample should be taken from the surface of the vaginal portion of the cervix and from the walls of the cervical canal)), as well as collection of a detailed family history to identify diseases requiring treatment and to determine existing risks. Pregnancy must be excluded.

In case of suspected undiagnosed vaginal bleeding, additional investigations are required.

During treatment with the medicinal product, examinations are recommended once every 6 months.

If thromboembolic events (e.g., deep vein thrombosis, stroke, myocardial infarction) occurred at a young age in close relatives, the possibility of a coagulation disorder should be ruled out.

Women should also be informed that oral contraceptives do not protect against HIV infection (AIDS) or other sexually transmitted diseases.

The active ingredients in Debora are the progestogen cyproterone acetate and the estrogen ethinylestradiol, administered for 21 consecutive days each month. The composition of the medicinal product is similar to that of combined oral contraceptives (COCs).

Duration of use

Improvement in condition occurs no sooner than after 3 months. The physician should regularly assess the need for continued treatment (see section "Dosage and administration").

If any of the conditions or risk factors listed below are present, the benefits of using Debora must be weighed against the possible risks, taking into account individual patient characteristics, and discussed with the woman before she decides to use the medicinal product. In case of onset, worsening, or first occurrence of any of the conditions or risk factors listed below, women are advised to consult a physician. The physician must decide whether Debora should be discontinued.

Reasons for immediate discontinuation of Debora

− New onset or worsening migraine-like headache, unusually severe or prolonged headache;

− acute visual or auditory disturbances or other sensory disturbances;

− motor disturbances, especially paralysis (possible early signs of stroke), first signs of thrombophlebitis or thromboembolic events (e.g., unusual pain in the lower limbs or their swelling, stabbing pain on breathing or cough of unknown origin), chest pain or tightness;

− major surgical procedures (e.g., abdominal surgery, orthopedic procedures), surgical operations on the lower limbs, varicose vein treatment, or prolonged immobilization, e.g., after trauma or surgery. The intake of the medicinal product should be discontinued 6 weeks before a planned surgery. The medicinal product should not be resumed earlier than 2 weeks after full mobilization. In case of emergency surgery, thrombosis prophylaxis measures, such as subcutaneous heparin administration, are indicated;

− onset of jaundice, hepatitis, or generalized pruritus;

− increased frequency of epileptic seizures;

− elevated blood pressure;

− onset of severe depression;

− severe pain in the epigastric region or hepatomegaly;

− significant worsening of conditions known to be exacerbated by hormonal contraceptives or pregnancy;

− pregnancy.

Circulatory disorders

Women taking Debora have a higher risk of developing venous thromboembolism (VTE) compared to women not taking this medicinal product. The highest risk of VTE occurs during the first year of using Debora or when restarting treatment with this medicinal product or switching to it after a break of at least 1 month in tablet intake. VTE may result in fatal outcomes in 1–2% of cases.

Epidemiological studies have shown that the incidence of VTE in women taking Debora is 1.5–2 times higher than in women using combined oral contraceptives (COCs) containing levonorgestrel and may be similar to that with COCs containing desogestrel/gestodene/drospirenone.

Among patients receiving treatment with Debora, there may be women with an inherited increased risk of cardiovascular diseases, e.g., in polycystic ovary syndrome.

Epidemiological studies have demonstrated an association between COC use and an increased risk of arterial thrombotic and thromboembolic disorders (myocardial infarction, transient ischemic attack).

In rare cases, thrombosis in other blood vessels, e.g., in the hepatic, renal, mesenteric, cerebral, or retinal vessels, has been reported in women using hormonal contraceptives.

Symptoms of venous or arterial thrombotic events or stroke may include: unusual unilateral pain and/or swelling of the lower limbs; sudden severe chest pain, possibly radiating to the left arm; sudden shortness of breath; sudden onset cough; any unusual, severe, prolonged headache; sudden decrease or complete loss of vision; diplopia; speech disturbances or aphasia; vertigo; loss of consciousness with or without partial epileptic seizure; weakness or marked sudden numbness of half or part of the body; motor disturbances; "acute" abdomen.

Factors increasing the risk of venous thromboembolic events

• Age (risk increases with age);
• smoking (with heavy smoking, risk increases with age, especially in women aged 35 years or older. Women aged 35 years or older are advised to refrain from smoking if they wish to use Debora);
• complicated family history (e.g., venous thromboembolism in siblings or parents at a relatively young age). If there is or suspected hereditary predisposition, consultation with a physician is recommended before starting any hormonal contraceptive;
• prolonged immobilization, major surgical procedures, any surgical operations on the lower limbs, significant trauma. In these cases, discontinuation of the medicinal product is recommended (at least 4 weeks before planned surgery) and resumption of intake should not occur earlier than 2 weeks after full recovery of mobility. If Debora was not discontinued in advance, consideration should be given to prescribing antithrombotic therapy;
• obesity (body mass index >30 kg/m²).

Factors increasing the risk of arterial thromboembolic events or cerebrovascular disorders

• Age (risk increases with age);
• smoking (with heavy smoking, risk increases with age, especially in women aged 35 years or older. Women aged 35 years or older are advised to refrain from smoking if they wish to use Debora);
• dyslipoproteinemia;
• obesity (body mass index >30 kg/m²);
• arterial hypertension;
• migraine;
• heart valve disorders;
• atrial fibrillation;
• complicated family history (e.g., arterial thromboembolism in siblings or parents at a relatively young age). If hereditary predisposition is suspected, consultation with a physician is recommended before starting any hormonal contraceptive.

Other disorders that may be associated with circulatory disorders include: diabetes mellitus; systemic lupus erythematosus; hemolytic-uremic syndrome; chronic inflammatory bowel diseases (Crohn's disease or ulcerative colitis); and sickle cell anemia.

An increased risk of thromboembolism in the postpartum period should be considered (see section "Use during pregnancy or breastfeeding").

Increased frequency or worsening of migraine during the use of Debora (which may be a prodromal symptom of cerebral circulation disorder) is one of the reasons for possible immediate discontinuation of Debora.

Women receiving treatment with Debora must be warned to consult their physician if symptoms suggestive of thrombosis occur. In case of suspected or confirmed thrombosis, Debora should be discontinued. Due to the teratogenic effects of anticoagulants (coumarins), appropriate contraceptive methods should be used.

Women taking Debora for the treatment of severe acne, mild hirsutism, or androgenetic alopecia may have an increased risk of cardiovascular disorders, e.g., in combination with polycystic ovary syndrome.

Biochemical markers that may indicate inherited or acquired predisposition to venous or arterial thrombosis include: activated protein C resistance (APC resistance), hyperhomocysteinemia, deficiency of antithrombin III, deficiency of protein C, deficiency of protein S, antiphospholipid antibodies (anticardiolipin antibodies), lupus anticoagulant.

Arterial thromboembolic complications may be life-threatening or fatal.

It should be considered that the risk of thrombosis may increase due to synergistic effects of multiple risk factors, especially when several such factors are present or when any pronounced risk factor is present in the patient.

When assessing the benefit-risk ratio, it is recommended to consider that adequate treatment of the conditions mentioned above reduces their associated risk of thrombosis, and that the risk of thrombosis associated with pregnancy is higher than with COC use or use of Debora.

Debora should not be prescribed if the benefit-risk assessment is negative (see section "Contraindications").

Tumors

The most important risk factor for cervical cancer is persistent human papillomavirus (HPV) infection. Some epidemiological studies have suggested that long-term use of estrogen-progestogen combinations may increase this risk, but this remains controversial, as it is not fully established to what extent the study results accounted for confounding factors such as frequency of cervical screening and sexual behavior, including use of barrier contraception.

A meta-analysis based on 54 epidemiological studies indicates a slight increase in relative risk (RR = 1.24) of breast cancer in women using estrogen-progestogen combinations.

An important factor is the age at which women discontinued COC use; the frequency of breast cancer diagnosis increases with age and is independent of the duration of estrogen-progestogen combination use.

This increased risk gradually disappears within 10 years after stopping estrogen-progestogen combination use. Since breast cancer is rare in women under 40 years of age, the increase in diagnosed cases among current or recent users of estrogen-progestogen combinations is small relative to the overall risk of breast cancer. These study results do not provide evidence of a causal relationship. The increased risk may be due to earlier diagnosis of breast cancer in users of estrogen-progestogen combinations, biological effects of the combination, or a combination of both factors. A tendency has been observed that breast cancer diagnosed in women who have ever used estrogen-progestogen combinations is clinically less severe than in those who have never used them.

In isolated cases, benign and, even more rarely, malignant liver tumors have been observed in women using hormonal substances such as those contained in Debora, which in some cases led to life-threatening intra-abdominal hemorrhage. In case of complaints of severe epigastric pain, hepatomegaly, or signs of intra-abdominal hemorrhage, the possibility of a liver tumor should be considered in the differential diagnosis during estrogen-progestogen combination use.

Malignant tumors may be life-threatening or fatal.

Other disorders

Women with hypertriglyceridemia or a family history of this condition may have an increased risk of pancreatitis when using estrogen-progestogen combinations.

Although slight increases in blood pressure have been reported in many women using estrogen-progestogen combinations (such as, for example, estrogen-progestogen combinations or Debora), clinically significant increases are rare. If persistent clinically significant arterial hypertension develops during treatment with Debora, the medicinal product should be discontinued and antihypertensive treatment initiated. If normal blood pressure levels are achieved after antihypertensive therapy, resumption of Debora may be considered, if deemed appropriate.

The occurrence or worsening of the following conditions has been reported during pregnancy and with use of estrogen-progestogen combinations, although a causal relationship has not been established: cholestatic jaundice and/or pruritus, gallstone formation, porphyria, systemic lupus erythematosus, hemolytic-uremic syndrome, Sydenham's chorea, herpes gestationis, hearing loss associated with otosclerosis, epilepsy.

In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms.

Acute or chronic liver function disorders may require temporary discontinuation of Debora until liver function parameters normalize. Recurrence of cholestatic jaundice and/or pruritus that first occurred during pregnancy or previous use of sex steroids also requires discontinuation of Debora.

Although estrogen-progestogen combinations may affect insulin resistance and glucose tolerance, there are currently no data on the need to modify therapeutic regimens in diabetic patients using low-dose estrogen-progestogen combinations (containing <0.05 mg ethinylestradiol). However, diabetic patients using Debora should be under close medical supervision.

Crohn's disease and ulcerative colitis have been associated with the use of estrogen-progestogen combinations.

Depressed mood and depression are well-known adverse reactions that may occur during use of hormonal contraceptives (see section "Adverse reactions"). Depression can be a serious condition and is a well-known risk factor for suicidal behavior and suicide. Women should be advised to consult a physician if mood changes or symptoms of depression occur, including soon after starting treatment.

Chloasma may sometimes occur, particularly in women with a history of chloasma gravidarum. Women prone to chloasma should avoid exposure to sunlight or ultraviolet radiation during treatment with Debora.

Reduced efficacy

The contraceptive efficacy of Debora may be reduced in case of missed tablet intake (see section "Dosage and administration"), gastrointestinal disorders (see section "Dosage and administration"), or concomitant use with other medicinal products (see section "Interaction with other medicinal products and other forms of interaction").

Irregular bleeding

When using medicinal products containing estrogen/progestogen combinations, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. Evaluation of irregular vaginal bleeding should only be performed after an adaptation period (usually after 3 cycles of tablet intake).

If irregular bleeding persists after the adaptation period or occurs after a period of regular bleeding, non-hormonal causes of bleeding and the need for appropriate diagnostic measures, including evaluation to rule out tumors and pregnancy, should be considered. Diagnostic measures may include curettage.

Reduced menstrual flow is not pathological and may occur in some patients.

Absence of withdrawal bleeding during the tablet-free interval (7-day break) may occur in some women. Pregnancy is unlikely if Debora is taken according to the instructions in section "Dosage and administration." However, if Debora was not taken as directed before the first missed withdrawal bleeding or if withdrawal bleeding does not occur twice consecutively, pregnancy should be ruled out before continuing treatment with Debora.

After discontinuation of Debora, amenorrhea or oligomenorrhea may occur, especially if these conditions were present before starting treatment.

Lactose intolerance

Debora contains lactose monohydrate; therefore, the medicinal product should not be used in patients with rare hereditary intolerance to galactose, Lapp lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding

Pregnancy must be excluded before starting treatment with the medicinal product. The medicinal product is contraindicated during pregnancy. If pregnancy occurs during treatment with Debora, intake must be discontinued immediately; however, this is not a reason to terminate the pregnancy.

The medicinal product is contraindicated during breastfeeding. Cyproterone acetate and ethinylestradiol pass into breast milk and may enter the infant's body during breastfeeding.

Ability to affect reaction speed when driving or operating machinery

No effects of Debora on the ability to drive or operate machinery have been observed in patients using the medicinal product.

Method of Administration and Dosage

Deborah suppresses ovulation and thus exerts a contraceptive effect. Therefore, patients using Deborah should not use additional hormonal contraceptives, as this may lead to hormone overdose and is unnecessary for achieving effective contraception. For the same reason, women who wish to become pregnant should not take Deborah. To achieve the desired therapeutic and contraceptive effect, Deborah must be taken regularly.

Method of Administration

For oral use.

Dosage

Tablets should be taken daily according to the order indicated on the blister pack, approximately at the same time each day, with a small amount of liquid. One tablet should be taken daily for 21 consecutive days. The intake of tablets from each subsequent pack should begin after the completion of the 7-day drug-free interval, during which a menstruation-like bleeding usually occurs. This bleeding typically starts on the 2nd or 3rd day after the last tablet and may continue until the start of the next pack.

Contraceptive protection begins from the first day of tablet intake and continues throughout the 7-day drug-free interval. Therefore, concurrent use of other hormonal contraceptives should be discontinued.

Initiating Deborah

• If hormonal contraceptives have not been used previously (in the past month):

Tablet intake should begin on the first day of the natural cycle (i.e., the first day of menstrual bleeding), one tablet daily for 21 consecutive days. If intake starts on days 2–5, an additional contraceptive method (e.g., barrier method) should be used for the first 7 days of tablet intake.

Only women with amenorrhea may start taking the drug immediately as prescribed by a physician. In this case, the first day of tablet use is considered the first day of the menstrual cycle, and the cycle count continues according to the recommendations provided below.

Intake of tablets from each subsequent pack should begin after the completion of the 7-day drug-free interval. For effective contraceptive protection, Deborah must be taken strictly according to the instructions. If no menstruation-like bleeding occurs during the drug-free interval, pregnancy must be ruled out before starting tablets from the next pack.

• Switching from another combined oral contraceptive (COC) with a 21-day regimen:

Begin taking Deborah tablets the day after completing the previous COC pack. In this case, additional contraceptive methods are not required.

• Switching from another combined oral contraceptive (COC) with a 28-day regimen:

Begin taking Deborah tablets the day after taking the last hormone-containing tablet of the previous COC. In this case, additional contraceptive methods are not required.

• Switching from a progestogen-only method (mini-pill):

Deborah should be started on the first day of menstrual bleeding, even if the progestogen-only tablet has already been taken that day. In this case, additional contraceptive methods are not required.

Continued use of the progestogen-only method should be discontinued.

• After childbirth or abortion:

Deborah may be started 21 days after childbirth, provided there have been no complications. A barrier method of contraception is recommended for the first 7 days of tablet intake. Since the first ovulation after childbirth may precede the first menstrual bleeding, additional contraceptive methods are recommended between childbirth and the start of the first Deborah cycle. After a first-trimester abortion, Deborah may be started immediately. In this case, additional contraceptive methods are not required.

Duration of Use

Clinical improvement occurs no sooner than after 3 months. The physician should regularly assess the need for continued treatment.

The duration of treatment depends on the severity of androgenization symptoms and the response to therapy. Acne and seborrhea typically resolve earlier than hirsutism symptoms. It is recommended to continue taking Deborah for at least 3–4 cycles after symptom resolution.

If there is no response or inadequate response to treatment—severe acne or seborrhea for at least 6 months, or hirsutism for at least 12 months—the treatment approach should be reevaluated.

If androgenization symptoms resolve but contraception is still needed, switching to a low-dose oral contraceptive should be considered. If androgenic symptoms recur, treatment with Deborah may be resumed. When reinitiating Deborah therapy (after at least a 4-week interval without tablets), the increased risk of venous thromboembolism (VTE) should be considered (see section "Special Warnings and Precautions for Use").

Missed Dose Instructions

If a woman forgets to take a Deborah tablet at the usual time, she should take it within 12 hours. All subsequent tablets from the same pack should be taken at the usual time. In this case, contraceptive efficacy is not reduced.

If the delay in taking the missed tablet exceeds 12 hours, the last missed tablet should be taken as soon as possible, even if this means taking two tablets at the same time. Then continue taking tablets at the usual time. In this case, contraceptive protection may be reduced, and an additional non-hormonal contraceptive method (other than calendar or temperature methods) should be used for the next 7 days.

If one or more tablets were missed during the last 7 days of a pack, the next pack should be started immediately after finishing the previous one, with no drug-free interval. Menstruation-like bleeding is unlikely before completing the second pack, although spotting or breakthrough bleeding may occur during tablet intake. If the expected menstruation does not occur during the drug-free interval after the second pack, pregnancy must be ruled out before starting the next pack.

Gastrointestinal Disorders

Vomiting or severe diarrhea may result in incomplete absorption of the active ingredients. In such cases, additional non-hormonal contraceptive methods (other than calendar or temperature methods) should be used during the episode and for the following 7 days. If the 7-day period overlaps with the end of a pack, the next pack should be started immediately without a break. Menstruation-like bleeding is unlikely before completing the second pack, although spotting or breakthrough bleeding may occur. If the expected menstruation does not occur during the drug-free interval after the second pack, pregnancy must be ruled out before starting the next pack. If vomiting or severe diarrhea occurs within 3–4 hours after taking a tablet, follow the missed dose instructions above. Consider alternative contraceptive methods if prolonged gastrointestinal disorders are expected.

Elderly Patients

Deborah is not indicated after menopause.

Hepatic Impairment

Deborah is contraindicated in women with severe liver disease until liver function tests return to normal (see section "Contraindications").

Renal Impairment

Deborah has not been specifically studied in patients with renal impairment. Available data do not indicate a need to modify the dosing regimen in this patient group.

Children

The drug is indicated for use only after regular menstruation has been established, and only as prescribed by a physician.

Overdose

Overdose may cause nausea, vomiting, and slight vaginal bleeding after discontinuation in young women. Vaginal bleeding may occur in girls even before menarche in case of accidental or unintentional drug intake. There is no specific antidote; treatment is symptomatic.

Adverse reactions.

The most commonly observed adverse reactions associated with the use of the medicinal product Debora are nausea, abdominal pain, weight gain, headache, depression, depressed mood, mood changes, breast tenderness, and breast tension. These occur in ≥ 1% to < 10% of all users.

For all women using the Debora preparation, there is an increased risk of developing venous or arterial thromboembolism (see section "Special precautions"). Additional factors (smoking, arterial hypertension, coagulation or lipid metabolism disorders, overweight, varicose veins, history of phlebitis and thrombosis) may contribute to a further increase in this risk (see section "Special precautions").

Information on other serious adverse reactions, such as liver tumors, cervical cancer, and breast cancer, is also provided in the section "Special precautions".

The adverse reactions listed below occurred during the use of Debora; however, their relationship to the use of the drug has neither been proven nor ruled out:

Description of individual adverse reactions

An increased risk of venous or arterial thrombotic and thromboembolic events, including myocardial infarction, stroke, transient ischaemic attacks, venous thrombosis, and pulmonary embolism, has been observed in women taking estrogen-progestogen combinations, as described in more detail in the section "Special precautions for use".

The following serious adverse reactions have been observed in women using estrogen-progestogen combinations, which are also described in the section "Special precautions for use":

• venous thromboembolism;
• arterial thromboembolism;
• arterial hypertension;
• liver tumours (benign or malignant);
• development or worsening of diseases for which a definite link to estrogen-progestogen combination use has not been established: Crohn's disease, ulcerative colitis, epilepsy, uterine fibroids, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham's chorea, haemolytic-uraemic syndrome, cholestatic jaundice;
• chloasma;
• acute or chronic disorders of liver function, which may require discontinuation of estrogen-progestogen combinations until liver function parameters return to normal;
• in women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

The incidence of breast cancer is slightly increased in individuals using estrogen-progestogen combinations. Since breast cancer is rare in women under 40 years of age, the additional risk of developing breast cancer is small in relation to the overall risk. A causal relationship with the use of estrogen-progestogen combinations has not been established. For further information, see the sections "Contraindications" and "Special precautions for use".

If symptoms of hirsutism have recently worsened significantly in women suffering from this condition, the underlying causes (androgen-producing tumour, adrenal enzyme disorders) must be investigated by differential diagnosis.

Interactions

Breakthrough bleeding and/or reduced contraceptive efficacy may occur due to interactions between other medicinal products (enzyme inducers) and estrogen-progestogen combinations (see section "Interaction with other medicinal products and other forms of interaction").

Effect on laboratory parameters

Erythrocyte sedimentation rate may increase in the absence of disease. Cases of increased serum levels of copper and iron, as well as leukocyte alkaline phosphatase, have been reported.

Other effects

In isolated cases, disturbances in folate and tryptophan metabolism are possible.

When taken regularly, the drug Deborah exerts contraceptive action due to its active ingredients. Irregular intake of Deborah may lead to an irregular menstrual cycle. Regular intake of Deborah is very important, as it prevents irregular cycles and also prevents pregnancy (due to the potential effect of cyproterone acetate on the foetus).

Reporting suspected adverse reactions

Reporting suspected adverse reactions during post-marketing surveillance is very important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report suspected adverse reactions.

Shelf life

18 months.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging

21 tablets in a blister pack, 1 blister pack in a cardboard box.

Prescription status

Prescription only.

Manufacturer

San Pharmaceuticals Industries Ltd.

Manufacturer's address and location of operations

Baroda Highway, Halol, Gujarat, 389350, India.