Dezeria^® (Tablets) Instructions for Use

Marketing Authorization Holder

Binnopharm Group LLC (Russia)

Manufactured By

Laboratorios Leon Farma, S.A. (Spain)

Contact Information

BINNOPHARM GROUP LLC (Russia)

ATC Code

G03AC09 (Desogestrel)

Active Substance

Desogestrel (Rec.INN registered by WHO)

Dosage Form

Dezeria®

Film-coated tablets, 75 mcg: 28 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, round, biconvex. The cross-section shows a white or almost white core surrounded by one layer of the coating.

Excipients: tablet core lactose monohydrate, corn starch, povidone K30, D-alpha-tocopherol (vit. E), hydrated colloidal silicon dioxide, anhydrous colloidal silicon dioxide, stearic acid; finished film coating hypromellose 2910, polyethylene glycol, titanium dioxide (E171).

28 pcs. – blisters (1) – cardboard packs.

Clinical-Pharmacological Group

Gestagen for oral contraception

Pharmacotherapeutic Group

Sex hormones and modulators of the genital system; systemic hormonal contraceptives; progestogens

Pharmacological Action

Mechanism of action

Dezeria^® is a progestogen-containing oral contraceptive containing a progestogen (Desogestrel). Like other progestogen-containing oral contraceptives (mini-pills), Desogestrel is best suited for use during breastfeeding and for women for whom estrogens are contraindicated or who do not wish to take estrogens. Unlike mini-pills, the contraceptive effect of desogestrel is achieved mainly by suppressing ovulation. Other effects include an increase in cervical mucus viscosity.

Clinical efficacy and safety

In a study of desogestrel use over 2 cycles, the ovulation rate, determined by a progesterone level above 16 nmol/l for 5 consecutive days, was 1% (1/103) with a 95% CI: 0.02-5.29% in the group of all patients included in the study (patient error and method failure). Ovulation suppression was achieved from the 1st cycle of drug use. In this study, after discontinuation of the drug, after use for 2 cycles (56 consecutive days), ovulation occurred on average after 17 days (range 7-30 days). In a comparative efficacy study (which allowed missed pills to be taken for a maximum of 3 hours), the overall Pearl Index (an indicator reflecting the pregnancy rate per 100 women per year of contraceptive use) for desogestrel in the group of all patients included in the study was 0.4 (95% CI: 0.09-1.20) compared to 1.6 (95% CI: 0.42-3.96) for 0.03 mg levonorgestrel. The Pearl Index for desogestrel is comparable to the Pearl Index of combined oral contraceptives in the general population of oral contraceptive users. Taking desogestrel leads to a decrease in serum estradiol levels to values characteristic of the early follicular phase. At the same time, no clinically significant changes in carbohydrate, lipid metabolism, and hemostasis parameters were identified.

Pharmacokinetics

Absorption

After oral administration, Desogestrel is rapidly absorbed and converted into the biologically active metabolite etonogestrel. At steady state, the C_max of etonogestrel in serum is reached 1.8 hours after oral tablet intake, and the absolute bioavailability of etonogestrel is approximately 70%.

Distribution

Etonogestrel is 95.5-99% bound to serum proteins, primarily to albumin and to a lesser extent to sex hormone-binding globulin.

Metabolism

Desogestrel is converted by hydroxylation and dehydrogenation into the active metabolite etonogestrel. Etonogestrel is metabolized via the formation of sulfate and glucuronide conjugates.

Excretion

Etonogestrel is eliminated with a T_1/2 of about 30 hours, both after single and multiple doses. Steady-state plasma concentrations are reached after 4-5 days. The serum clearance after intravenous administration of etonogestrel is approximately 10 L/h. Etonogestrel and its metabolites are excreted both as free steroids and as conjugates, by the kidneys and intestines (in a ratio of 1.5:1). In breastfeeding women, etonogestrel is excreted in breast milk with a milk/serum ratio of 0.37-0.55. Therefore, with an approximate breast milk intake of 150 ml/kg/day, a newborn may receive 0.01-0.05 mcg of etonogestrel per kg of body weight per day.

Indications

Adults aged 18 years and older

• For contraception.

ICD codes

Dosage Regimen

Orally, 1 tablet/day daily for 28 days. Each subsequent package is started immediately after the previous package is finished.

Special patient groups

Patients with renal impairment

Clinical studies in patients with renal failure have not been conducted.

Patients with hepatic impairment

Clinical studies in patients with hepatic failure have not been conducted.

Since the metabolism of steroid hormones may be impaired in patients with hepatic insufficiency, the use of Dezeria^® is not indicated for women until liver function tests normalize (see section “Contraindications”).

Children

The safety and efficacy of desogestrel in adolescents under 18 years of age have not been established. No data available.

Method of administration

To achieve contraceptive efficacy, Dezeria^® should be taken in accordance with the instructions below.

The tablets should be taken orally in the order indicated on the package, every day at approximately the same time, with a small amount of liquid if necessary. One tablet should be taken daily for 28 days. Each subsequent package is started immediately after the previous package is finished.

Starting Dezeria^®

In the absence of prior use of hormonal contraceptives (within the last month)

Tablet intake should be started on the 1st day of the menstrual cycle (on the 1st day of menstrual bleeding). It is permissible to start on days 2-5, but then during the first cycle, for the first 7 days of taking the tablets, it is recommended to additionally use a barrier method of contraception.

Switching from a combined hormonal contraceptive (combined oral contraceptive, vaginal ring, or transdermal patch )

The woman should start taking Dezeria^® preferably on the day after taking the last active tablet of the combined oral contraceptive (the last tablet containing the active substance) or on the day of removal of the vaginal ring or patch. In these cases, there is no need for additional contraception.

At the latest, a woman can also start taking Dezeria^® on the day after the end of the usual tablet-free interval, patch-free interval, ring-free interval, or on the day after taking the placebo tablets of the previous combined oral contraceptive (i.e., on the day when she would have started a new pack of the combined oral contraceptive, inserted a new ring, or applied a new patch), but during the first 7 days of taking the tablets, it is recommended to use an additional barrier method of contraception.

Switching from other progestogen-containing drugs (mini-pill, implant injection, or progestogen-releasing IUD)

A woman taking a mini-pill can switch to Dezeria^® on any day. A woman using an implant or IUD – on the day of their removal. A woman using injectable forms of contraceptives – on the day the next injection is due. In all these cases, an additional method of contraception is not required.

Use of the drug after a first-trimester abortion

After a first-trimester abortion, it is recommended to start taking the drug immediately; an additional method of contraception is not required.

After childbirth or a second-trimester abortion

The drug can be taken no earlier than 21-28 days after a second-trimester abortion and no earlier than the 6th week after childbirth. If starting the drug later, it is necessary to additionally use a barrier method of contraception during the first 7 days of taking the tablets. However, if a woman has had sexual intercourse after childbirth or abortion before starting Dezeria^®, pregnancy should be ruled out before starting the drug, or the woman should wait for the first menstruation.

For breastfeeding women, see the section “Pregnancy and Lactation”.

Missed dose

Contraceptive protection may be reduced if the interval between taking two tablets is more than 36 hours. If the delay in taking a tablet is less than 12 hours, the missed tablet should be taken as soon as the woman remembers, and the next tablet should be taken at the usual time. If the delay in taking a tablet is more than 12 hours, the woman should follow the above recommendations and also use an additional method of contraception for the next 7 days. If tablets were missed in the very first week of taking the drug and sexual intercourse occurred during the week before the missed dose, pregnancy should be ruled out.

Recommendations in case of gastrointestinal disorders

In case of severe gastrointestinal disorders (vomiting, diarrhea), absorption may be incomplete, and in this case, additional contraceptive methods should be used. If vomiting occurs within 3-4 hours after intake, absorption may be incomplete. In this case, it is necessary to follow the recommendations regarding missed tablets.

Adverse Reactions

Summary of the safety profile

The most frequent adverse reaction (AR) reported in clinical studies of desogestrel was bleeding irregularity. Up to 50% of women taking Desogestrel reported acyclic bleeding of varying degrees. Since Desogestrel, unlike other progestogen-only contraceptives, suppresses ovulation in almost 100% of cases, irregular bleeding is noted more often than with other progestogen-only contraceptives. In 20-30% of women, such bleeding may become more frequent, while in another 20%, bleeding may become less frequent or absent altogether. Furthermore, the duration of vaginal bleeding may increase. After 2 cycles of drug use, the frequency of acyclic bleeding decreases. Informing, monitoring by a doctor, and keeping a menstrual diary can increase treatment compliance through understanding the nature of bleeding. Other most frequent ARs (>2.5%) in clinical studies of desogestrel were: acne, mood swings, breast pain, nausea, and weight gain.

Tabulated summary of adverse reactions

ARs that may occur with the use of desogestrel are distributed by system-organ class with an indication of their frequency of occurrence according to WHO recommendations: common (≥1/100 but <1/10), uncommon (≥1/1000 but <1/100), rare (≥1/10000 but <1/1000).

In addition, hypersensitivity reactions (including angioedema and anaphylaxis) have been reported during post-marketing surveillance.

Various (serious) ARs have been observed in women using (combined) oral contraceptives. These include venous and arterial thrombosis and thromboembolism, hormone-dependent tumors (e.g., breast cancer), and chloasma (see section “Special Precautions”).

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals are encouraged 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 desogestrel or any of the excipients of the drug;
• Established or suspected pregnancy;
• Current or history of venous thromboembolism (including deep vein thrombosis of the leg, pulmonary embolism);
• Current or history of severe liver disease (until liver function tests normalize);
• Established or suspected malignant hormone-dependent tumors;
• Vaginal bleeding of unknown etiology;
• Age under 18 years (safety and efficacy of desogestrel use in adolescents under 18 years of age have not been established).

Use in Pregnancy and Lactation

Pregnancy

The use of the drug during pregnancy is contraindicated.

Results of preclinical studies have shown that very high doses of progestogens can cause masculinization of the female fetus.

Extensive epidemiological studies have not revealed an increased risk of birth defects in children whose mothers took oral contraceptives before pregnancy, nor a teratogenic effect with unintentional use of oral contraceptives in early pregnancy. Pharmacological data from various combined oral contraceptives containing Desogestrel also did not show an increased risk.

Breastfeeding period

Desogestrel does not affect the quantity or quality (concentrations of proteins, lactose, or fats) of breast milk. However, small amounts of etonogestrel are excreted in breast milk. As a result, the infant may receive 0.01-0.05 mcg of etonogestrel per kg of body weight per day (based on an intake of 150 ml/kg/day of breast milk).

There are limited long-term follow-up data on children whose mothers started taking Desogestrel within 4-8 weeks after childbirth. The duration of breastfeeding was 7 months, and the children were observed until they reached the age of 1.5 (n=32) or 2.5 years (n=14). Assessment of growth, physical and psychomotor development did not reveal any differences with toddlers whose mothers used copper intrauterine devices. The available data indicate that Desogestrel can be used during lactation. Nevertheless, the development and growth of the breastfed infant whose mother is using Desogestrel should be carefully observed.

Use in Hepatic Impairment

Contraindicated for use in the presence of current or history of severe liver disease (until liver function tests normalize).

Pediatric Use

Contraindication: age under 18 years (safety and efficacy of desogestrel use in adolescents under 18 years of age have not been established).

Special Precautions

The drug should be used with caution in the presence of any of the conditions/risk factors listed below; the benefit of using the progestogen and possible risks for each individual woman should be weighed. This should be discussed with the woman before she decides to start taking desogestrel. In case of worsening, exacerbation of the disease, or the first occurrence of any of these conditions, the woman should consult a doctor. The doctor should decide on the advisability of further use of desogestrel.

• Persistent hypertension developing while taking desogestrel, or if antihypertensive therapy is ineffective.
• Thromboembolic disorders, including in the history: the woman should be warned about the possibility of recurrence.
• Prolonged immobilization associated with surgery or illness.
• Since the biological influence of progestogens on the development of liver cancer cannot be excluded, an individual assessment of the benefit-risk ratio should be carried out when prescribing the drug to women with liver cancer.
• History of hepatic insufficiency.
• Chloasma, especially in women with a history of chloasma during pregnancy: women predisposed to chloasma should avoid exposure to sunlight or ultraviolet radiation while using desogestrel.

In the presence of any of the conditions or risk factors listed below, the advantages and possible harm of using progestogens should be carefully weighed. This issue should be discussed with the patient before starting desogestrel. In case of exacerbation of diseases, worsening of the condition, or the appearance of the first symptoms of the aforementioned conditions or risk factors, the patient should immediately consult a doctor. The doctor should decide on the need to discontinue desogestrel.

• The risk of breast cancer increases with age. During the use of combined oral contraceptives, the risk of a woman being diagnosed with breast cancer slightly increases. This increased risk gradually disappears within 10 years after stopping oral contraceptives; it is not related to the duration of use but depends on the woman’s age during the use of combined oral contraceptives. The expected number of diagnosed breast cancer cases among 10,000 women who used combined oral contraceptives (within 10 years after stopping their use), relative to women who never used them, for the same period, calculated for the respective age groups, is presented in the table below.

The risk in women using progestogen-containing contraceptives, for example, Desogestrel, is possibly similar to that when using combined oral contraceptives. However, data for progestogen-containing contraceptives are not as conclusive. Compared to the lifetime risk of developing breast cancer, the increase in risk associated with taking combined oral contraceptives is small. Breast cancer diagnosed in women using combined oral contraceptives tends to be less clinically advanced than cancer diagnosed in women who have never used combined oral contraceptives. The increased risk in women using combined oral contraceptives may be due to earlier diagnosis, biological effects of the drug, or a combination of these two factors.

• Since it is impossible to exclude the biological influence of progestogens on the development of liver cancer, an individual assessment of the benefit-risk ratio should be conducted when prescribing the drug to women with liver cancer.
• In case of acute or chronic liver function disorders, a woman should consult a specialist for examination and consultation.
• If persistent hypertension develops while taking desogestrel, or if antihypertensive therapy is ineffective with a significant increase in blood pressure, the possibility of discontinuing desogestrel should be considered.
• Epidemiological studies have established a connection between the use of combined oral contraceptives and an increased incidence of venous thromboembolism (VTE, deep vein thrombosis and pulmonary embolism). And although the clinical significance of these data for desogestrel as a contraceptive without an estrogen component is unknown, the use of desogestrel should be discontinued in case of thrombosis development. The possibility of discontinuing desogestrel should be considered in case of prolonged immobilization associated with surgery or illness. A woman with a history of thromboembolism should be informed about the possible recurrence.

• Although progestogens can affect peripheral tissue insulin resistance and glucose tolerance, there is no confirmation that it is necessary to change the therapeutic regimen in diabetic patients using progestogen-containing oral contraceptives. However, women with diabetes should be closely monitored during the first months of using the drug.
• The use of desogestrel leads to a decrease in serum estradiol levels to a level corresponding to the early follicular phase. To date, it is unknown whether this decrease has any clinically significant effect on bone mineral density.
• The prevention of ectopic pregnancy with traditional progestogen-containing oral contraceptives is not as effective as with the use of combined oral contraceptives, since ovulation often occurs when using progestogen-containing contraceptives. Although Desogestrel effectively suppresses ovulation, in case of amenorrhea or abdominal pain, ectopic pregnancy should be excluded during differential diagnosis.
• In rare cases, chloasma has developed, especially in women with a history of chloasma during pregnancy: women predisposed to chloasma should avoid exposure to sunlight or ultraviolet radiation while using desogestrel.
• During pregnancy and during the use of steroid sex hormones, the following conditions have been noted, although their relationship with progestogens has not been definitively established: jaundice and/or pruritus associated with cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; Sydenham’s chorea; herpes gestationis; hearing loss associated with otosclerosis; (hereditary) angioedema.

Medical Examinations/Consultations

Before prescribing the drug, a detailed history should be taken from the woman and a thorough gynecological examination should be performed to exclude pregnancy. Before prescribing the drug, the cause of menstrual cycle disorders, such as oligomenorrhea and amenorrhea, should be established. The interval between follow-up medical examinations is determined by the doctor in each individual case (frequency of examinations – at least once a year). If the prescribed drug may affect a latent or existing disease, an appropriate schedule of follow-up medical examinations should be drawn up.

Despite regular intake of desogestrel, irregular spotting may sometimes occur. If bleeding is very frequent and irregular, the possibility of using another method of contraception should be considered. If the above symptoms are persistent, then in this case, organic pathology must be excluded. The approach to amenorrhea during the use of the drug depends on whether the tablets were taken according to the instructions and may include a pregnancy test. In case of pregnancy, the drug should be discontinued.

Women should be informed that Desogestrel does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Reduced Effectiveness

The effectiveness of desogestrel may be reduced in case of missed tablets (see the “Dosage Regimen” section), gastrointestinal disorders (see the “Dosage Regimen” section), or in case of concomitant therapy that reduces the plasma concentration of etonogestrel – the active metabolite of desogestrel (see the “Drug Interactions” section).

Changes in Menstrual Pattern

During the use of progestogen-containing contraceptives, some women may experience more frequent or prolonged vaginal bleeding, while other women may experience less frequent bleeding or its complete cessation. These changes are often the reason why a woman refuses this method of contraception or stops strictly following the doctor’s instructions. During detailed consultation with women who have decided to start taking desogestrel, the doctor should discuss the possibility of such changes in the menstrual cycle pattern. The assessment of vaginal bleeding should be based on the clinical picture and may include examination to exclude malignant neoplasms or pregnancy.

Follicle Development

When taking all low-dose hormonal contraceptives, follicle development occurs; occasionally, the follicle size may reach sizes exceeding those in a normal cycle. Generally, these enlarged follicles disappear spontaneously. This is often asymptomatic; in some cases, mild lower abdominal pain is noted. Surgical intervention is rarely required.

Laboratory Tests

Data obtained for combined oral contraceptives have shown that the use of hormonal contraceptives can affect the results of some laboratory tests, including biochemical parameters of liver, thyroid, adrenal, and kidney function, levels of (transport) proteins in serum, for example, corticosteroid-binding globulin, lipid/lipoprotein fractions, carbohydrate metabolism parameters, and parameters of blood coagulation and fibrinolysis. Usually, these changes remain within normal limits. It is unknown to what extent this also applies to progestogen-containing contraceptives.

Excipients

The drug contains no more than 55 mg of 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

Based on the pharmacodynamic profile, Desogestrel is not considered to affect the ability to drive vehicles and mechanisms.

Overdose

No serious side effects have been reported as a result of overdose.

Symptoms: nausea, vomiting, and in young girls – minor vaginal bleeding.

Treatment: there are no antidotes, further treatment is symptomatic.

Drug Interactions

To determine possible interactions, it is necessary to read the instructions for use of concomitant drugs.

Interactions of oral contraceptives with other drugs can lead to “breakthrough” bleeding and/or reduced contraceptive effectiveness. The following interactions have been described in the literature (mainly with combined contraceptives, but sometimes also reported for progestogen-containing contraceptives).

Hepatic metabolism: interaction with medicinal or herbal drugs – inducers of microsomal enzymes, primarily cytochrome P450 (CYP) enzymes, is possible, which can lead to increased clearance and decreased concentration of sex hormones in plasma, and to reduced effectiveness of oral contraceptives, including desogestrel. Such drugs include those containing phenytoin, phenobarbital, primidone, bosentan, carbamazepine, rifampicin; and also, possibly, oxcarbazepine, rifabutin, topiramate, felbamate, griseofulvin; some HIV protease inhibitors (e.g., ritonavir and nelfinavir) and non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz), and herbal preparations containing St. John’s wort (Hypericum perforatum).

Enzyme induction can occur after several days of drug use. Maximum enzyme induction is usually observed within several weeks. After discontinuation of the drug therapy, enzyme induction may continue for approximately 28 days. When used concomitantly with hormonal contraceptives, many combinations of HIV protease inhibitors (e.g., nelfinavir) and non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine) and/or combinations with drugs for the treatment of hepatitis C virus (e.g., boceprevir, telaprevir) can increase or decrease the plasma concentration of progestins, including etonogestrel – the active metabolite of desogestrel. In some cases, the overall effect of these changes may be clinically significant. Women receiving treatment with one of the above-mentioned medicinal or herbal drugs that induce microsomal liver enzymes should be informed that the effectiveness of desogestrel may be reduced. During concomitant use of drugs that induce microsomal liver enzymes and for 28 days after their discontinuation, a barrier method of contraception should be used in addition to taking desogestrel. For long-term treatment with drugs that induce microsomal enzymes, the use of an alternative method of contraception not affected by drugs that induce microsomal enzymes should be considered. Concomitant use of strong (e.g., ketoconazole, itraconazole, clarithromycin) or moderate (e.g., fluconazole, diltiazem, erythromycin) CYP3A4 inhibitors may increase the serum concentration of progestins, including etonogestrel – the active metabolite of desogestrel.

When using activated charcoal, the absorption of desogestrel from the tablet may be reduced and, consequently, contraceptive effectiveness may be reduced. In such a case, the recommendations regarding missed tablets should be followed (see the “Dosage Regimen” section).

Hormonal contraceptives can affect the metabolism of other drugs. Accordingly, the concentrations of drugs in plasma and tissues may increase (e.g., cyclosporine) or decrease (e.g., lamotrigine).

Storage Conditions

The drug should be stored 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.