Lactinet®-richter

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LACTINET®-RICHTER (LACTINETTE®-RICHTER)

Composition:

active substance: desogestrel;

1 film-coated tablet contains 0.075 mg of desogestrel;

excipients: alpha-tocopherol, colloidal anhydrous silicon dioxide, stearic acid, povidone K-30, potato starch, lactose monohydrate; coating composition: Oparay II 85F28751 white: talc, polyethylene glycol 3000, titanium dioxide, E 171, polyvinyl alcohol.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex, film-coated tablets, white or almost white, approximately 5.5 mm in diameter, marked with "D" on one side and "75" on the other.

Pharmacotherapeutic group. Systemic hormonal contraceptives, progestogens. ATC code G03A C09.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Lactinet®-Richter film-coated tablets are a progestogen-only contraceptive containing desogestrel. Like other progestogen-only contraceptives, Lactinet®-Richter can be used by women who cannot or do not wish to take estrogens. Unlike conventional progestogen-only contraceptives, the contraceptive effect of Lactinet®-Richter film-coated tablets is primarily achieved through inhibition of ovulation. Additional effects include increased viscosity of cervical mucus.

Clinical Efficacy and Safety

In a two-cycle study where ovulation was confirmed by a progesterone level above 16 nmol/L for five consecutive days, ovulation was observed in 1% (1/103), with a 95% confidence interval of 0.02%–5.29%, in the group initiating treatment (users and those for whom the method failed). Suppression of ovulation was observed from the first treatment cycle. In this study, after discontinuation of 0.075 mg desogestrel tablets administered for two cycles (56 consecutive days), ovulation occurred on average on day 17 (range: day 7 to day 30).

In a comparative efficacy study (allowing for delayed tablet intake of up to 3 hours after the scheduled time), the Pearl Index for 0.075 mg desogestrel tablets was 0.4 (95% CI: 0.09–1.2) in the group initiating treatment, compared to 1.6 for 30 µg levonorgestrel (95% CI: 0.42–3.96).

Thus, the Pearl Index for 0.075 mg desogestrel tablets is comparable to that established for combined oral contraceptives (COCs) in the general population using COCs.

Administration of 0.075 mg desogestrel tablets results in a reduction of estradiol levels to values typical of the early follicular phase. No clinically significant effects on carbohydrate metabolism, lipid metabolism, or hemostasis were observed.

Children

Clinical data on efficacy and safety in adolescents under 18 years of age are lacking.

Pharmacokinetics

Absorption

After oral administration, Lactinet®-Richter desogestrel tablets, film-coated, are rapidly absorbed and metabolized to etonogestrel. At steady state, peak plasma concentration is reached 1.8 hours after tablet administration; the absolute bioavailability of etonogestrel is approximately 70%.

Distribution

Etonogestrel is 95.5–99% bound to plasma proteins, primarily to albumin and to a lesser extent to sex hormone-binding globulin (SHBG).

Biotransformation

Desogestrel is metabolized via hydroxylation and dehydrogenation to its active metabolite, etonogestrel. Etonogestrel is primarily metabolized by cytochrome P450 3A (CYP3A) isoenzymes, followed by formation of sulfate and glucuronide conjugates.

Elimination

The mean elimination half-life of etonogestrel is approximately 30 hours, regardless of whether it was administered repeatedly or as a single dose. Steady-state plasma levels are achieved within 4–5 days. After intravenous administration, the plasma clearance of etonogestrel is approximately 10 L/h. Etonogestrel and its metabolites are excreted in the form of free steroids or conjugates in urine and feces (in a ratio of 1.5:1). In lactating women, etonogestrel passes into breast milk at a milk-to-plasma ratio of 0.37–0.55. Based on these data and considering that an infant consumes approximately 150 mL of milk per kg body weight per day, the infant may receive about 0.01–0.05 micrograms of etonogestrel per day.

Special Patient Groups

Renal Impairment

Pharmacokinetic studies of desogestrel in patients with renal disease have not been conducted.

Hepatic Impairment

Pharmacokinetic studies of desogestrel in patients with hepatic disease have not been conducted. However, it should be considered that hepatic impairment may reduce the metabolism of steroid hormones.

Ethnic Groups

Comparative pharmacokinetic studies of desogestrel across different ethnic groups have not been conducted.

Clinical characteristics.

Indications.

Contraception.

Contraindications.

• Thromboembolic venous diseases in the active phase.
• Previous or existing severe liver diseases until normalization of liver function tests.
• Diagnosed or suspected hormone-dependent malignant neoplasms.
• Vaginal bleeding of unknown etiology.
• Hypersensitivity to the active substance or to any of the excipients of the medicinal product Lactinet®-Richter.

Interaction with other medicinal products and other forms of interaction.

Interactions

Note: Information regarding the concurrently used medicinal product should be consulted to identify potential interactions.

Effect of other medicinal products on Lactinet®-Richter.

An interaction is possible with medicinal products that induce microsomal enzymes, resulting in increased clearance of sex hormones, which in turn may lead to breakthrough bleeding and/or loss of contraceptive efficacy.

Therapy

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

Short-term treatment

Women taking medicinal and herbal products that induce hepatic enzymes should be informed that the efficacy of Lactinet®-Richter may be reduced; therefore, they should temporarily use an additional barrier method of contraception alongside Lactinet®-Richter. The barrier method should be used throughout the entire period of treatment with the enzyme-inducing agent and for an additional 28 days after discontinuation of the agent.

Long-term treatment

For women undergoing long-term therapy with medicinal products that induce liver enzymes, it is recommended to use an alternative method of contraception that is not affected by enzyme-inducing medicinal products.

Substances that increase the clearance of sex hormones (reduced contraceptive efficacy due to enzyme induction), e.g., barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin, efavirenz, and possibly felbamate, griseofulvin, oxcarbazepine, topiramate, rifabutin, and herbal preparations containing St John's wort (Hypericum perforatum).

Substances with variable effects on the clearance of contraceptive hormones

Concomitant use of hormonal contraceptives with many HIV protease inhibitors (e.g., ritonavir, nelfinavir) and non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine) and/or combinations with antiviral agents for hepatitis C virus (HCV) (e.g., boceprevir, telaprevir) may increase or decrease plasma concentrations of progestins. The net effect of these changes may be clinically significant in some cases.

Therefore, information regarding the medical use of the medicinal product for the treatment of HIV/HCV should be consulted to identify potential interactions and any other recommendations. In case of any doubts, women should additionally use a barrier method of contraception during therapy with protease inhibitors or non-nucleoside reverse transcriptase inhibitors.

Substances that reduce the clearance of sex hormones (enzyme inhibitors)

Concomitant use with strong (e.g., ketoconazole, itraconazole, clarithromycin) or moderate (e.g., fluconazole, diltiazem, erythromycin) inhibitors of CYP3A4 may lead to increased serum concentrations of progestins, including etonogestrel, the active metabolite of desogestrel.

Effect of Lactinet®-Richter on other medicinal products.

Hormonal contraceptives may affect the metabolism of other medicinal products. Consequently, their plasma and tissue concentrations may either increase (e.g., cyclosporine) or decrease (e.g., lamotrigine).

Special precautions.

Medical examination

Before prescribing the drug, a thorough medical history should be obtained and a gynecological examination performed to exclude definite pregnancy. Prior to prescribing, the causes of menstrual cycle disorders (oligomenorrhea and amenorrhea) should be clarified. The frequency of follow-up examinations should be determined individually by the physician for each patient. If during treatment there is a likelihood of influence on the course of latent or overt disease (see section "Special precautions"), appropriate regular monitoring examinations should be scheduled.

Despite regular use of Lactinet®-Richter, dysfunctional bleeding may occur. If bleeding occurs very frequently and irregularly, consideration should be given to switching to another method of contraception. If symptoms persist, functional disorders should be ruled out.

Monitoring of amenorrhea during treatment depends on adherence to the instructions for taking the tablets and may include a pregnancy test.

If pregnancy occurs, the drug should be discontinued immediately.

Women should be advised that Lactinet®-Richter does not protect against HIV infection (AIDS) or other sexually transmitted infections.

Warning.

In the presence of any of the conditions/risk factors listed below, the benefits of using progestogen and the possible risks for each individual woman should be carefully evaluated and discussed with her before deciding to start treatment with Lactinet®-Richter. In case of exacerbation, recurrence, or initial manifestation of any of these conditions, the woman should consult her physician. The physician must decide whether treatment with Lactinet®-Richter should be continued.

Overall, the risk of developing breast cancer increases with age. During use of combined oral contraceptives (COCs), the risk of developing breast cancer is slightly increased. This elevated risk gradually decreases over 10 years after discontinuation of COCs, but it is related not to the duration of COC use, but to the woman's age at the time of COC use. The expected number of diagnosed cases per 10,000 women who used COCs (within 10 years after stopping) compared to women who never used COCs during the same period was calculated for corresponding age groups and is presented in the table below.

Age group	Expected number of cancer diagnoses among women using oral contraceptives	Expected number of cancer diagnoses among women not using oral contraceptives
16–19 years	4.5	4
20–24 years	17.5	16
25–29 years	48.7	44
30–34 years	110	100
35–39 years	180	160
40–44 years	260	230

The risk in women using progestogen-only oral contraceptives (POCs), such as Lactinet®-Richter, is likely comparable to that observed in women using combined oral contraceptives (COCs). However, data on POCs are not conclusive. Compared to the lifetime risk of developing breast cancer, the risk associated with COC use is low. In women using COCs, breast cancer is usually diagnosed at an earlier stage than in non-users. The increased risk in COC users may be explained by earlier diagnosis, the biological effect of the pills, or a combination of both factors.

Since a biological effect of progestogens on the development of liver cancer cannot be excluded, the benefit-risk ratio should be individually assessed in women with liver cancer.

Women with acute or chronic liver function disorders should be referred for examination and consultation with an appropriate specialist.

Epidemiological data indicate that the use of COCs is associated with an increased risk of venous thromboembolism (VTE, deep vein thrombosis and pulmonary embolism). Although the clinical significance of these findings with respect to desogestrel used in estrogen-free contraceptives is unknown, if thrombosis occurs, Lactinet®-Richter must be discontinued. Consideration should be given to discontinuing Lactinet®-Richter in cases of prolonged immobilization due to surgery or illness.

Women with a history of thromboembolic disorders should be informed about the possibility of recurrence.

Although progestogens may affect insulin resistance and glucose tolerance, there is currently no evidence to support the need for changes in treatment regimens for diabetic patients using progestogen-only contraceptives. However, patients with diabetes should be closely monitored during the first month of using the medication.

If persistent arterial hypertension develops during use of Lactinet®-Richter, or if blood pressure significantly increases and does not respond to antihypertensive therapy, discontinuation of Lactinet®-Richter should be considered.

Use of Lactinet®-Richter leads to a reduction in serum estradiol concentration to levels typical of the early follicular phase. To date, it is unknown whether this reduction has any clinically significant effect on bone mineral density.

Progestogen-only contraceptives are less effective in preventing ectopic pregnancy than combined oral contraceptives. This is explained by the fact that ovulation occurs relatively frequently when using progestogen-only contraceptives. Despite the fact that Lactinet®-Richter consistently suppresses ovulation, the possibility of pregnancy should be considered in differential diagnosis if a woman presents with amenorrhea or abdominal pain.

In rare cases, melasma may occur, particularly in women with a history of melasma of pregnancy. Women prone to melasma should avoid exposure to sunlight and ultraviolet radiation while taking Lactinet®-Richter.

The following conditions have been reported during pregnancy as well as during use of sex steroid hormones; a causal relationship with progestogen use 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; (hereditary) angioedema.

Depressed mood and depression are known adverse effects of hormonal contraceptives (see section "Adverse Reactions"). Depression can be severe and is a known risk factor for suicidal behavior and suicide. Women should be advised to contact their physician if they experience mood changes or depressive symptoms, including shortly after starting treatment.

The effectiveness of Lactinet®-Richter may be reduced if doses are missed (see section "Dosage and Administration"), if gastrointestinal disturbances occur (see section "Dosage and Administration"), or if certain concomitant medications that alter plasma concentrations of etonogestrel, the active metabolite of desogestrel, are used (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Lactinet®-Richter, film-coated tablets, contain 52.34 mg of lactose monohydrate and therefore should not be used in patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

Laboratory Tests.

Data are available on the effects of COCs on the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal, and kidney function, serum protein (carrier) levels such as corticosteroid-binding globulin, lipid/lipoprotein fractions, carbohydrate metabolism parameters, and coagulation and fibrinolysis parameters. Changes are usually within normal ranges. It is unknown to what extent this applies to progestogen-only contraceptives.

Use during pregnancy or breastfeeding.

Pregnancy

Lactinet®-Richter is not indicated during pregnancy. If pregnancy occurs in women using Lactinet®-Richter, the medication should be discontinued immediately.

Animal studies have shown that very high doses of compounds with progestogenic activity may cause masculinization of female offspring.

Extensive epidemiological studies have not shown an increased risk of congenital malformations in children born to women who used COCs prior to pregnancy, nor teratogenic effects from inadvertent COC use in early pregnancy. Pharmacovigilance data on various COCs containing desogestrel also do not indicate any increased risk.

Breastfeeding Period

According to clinical data, 0.075 mg desogestrel tablets do not affect the production or quality of breast milk (concentration of protein, lactose, or fat). However, according to rare post-marketing reports, a decrease in breast milk production has been observed during use of 0.075 mg desogestrel tablets. A small amount of etonogestrel (metabolite of desogestrel) passes into breast milk. As a result, the infant may receive 0.01–0.05 micrograms of the drug per kg body weight per day (based on an estimated milk intake of 150 ml/kg/day). Like other progestogen-only medications, Lactinet®-Richter can be used during breastfeeding.

Limited long-term data are available on children whose mothers started taking 0.075 mg desogestrel tablets between 4 and 8 weeks postpartum. These infants were breastfed up to 7 months and followed up to 1.5 years (n = 32) or 2.5 years (n = 14). Assessments of growth, physical, and psychomotor development revealed no differences compared to infants whose mothers used a copper intrauterine device (IUD). Based on available data, Lactinet®-Richter can be used during breastfeeding. Nevertheless, careful monitoring of the infant's growth and development is necessary when the mother uses Lactinet®-Richter.

Fertility

Lactinet®-Richter is intended for pregnancy prevention. Information on fertility (ovulation) recovery is provided in the "Pharmacodynamics" section.

Ability to affect reaction speed when driving or operating machinery.

Lactinet®-Richter has no effect or negligible effect on the ability to drive vehicles or operate machinery.

Method of Administration and Dosage

Dosage

To achieve effective contraception, Lactinet®-Richter should be used according to the instructions (see "How to take Lactinet®-Richter" and "When to start taking Lactinet®-Richter").

Special Patient Groups

Renal Impairment

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

Hepatic Impairment

Clinical studies in patients with hepatic impairment have not been conducted. In cases of severe liver dysfunction, steroid hormone metabolism may be impaired; therefore, Lactinet®-Richter should only be prescribed after normalization of liver function tests (see section "Contraindications").

Method of Administration

For oral use.

How to take Lactinet®-Richter

Tablets should be taken daily at approximately the same time each day, ensuring that the interval between two consecutive tablets is always 24 hours. The first tablet should be taken on the first day of the natural menstrual cycle (the first day being the first day of menstrual bleeding). Subsequently, one tablet should be taken daily regardless of any possible bleeding. A new blister pack should be started the day after the tablets from the previous pack have been used up.

When to start taking Lactinet®-Richter

If no hormonal contraceptives were used previously (in the past month)

Tablet intake should begin on the first day of the woman’s natural menstrual cycle (the first day being the first day of menstrual bleeding). It is permissible to start taking the tablets between days 2 and 5 of the cycle; however, during the first cycle, a barrier method of contraception should be used for the first 7 days of tablet intake.

After first-trimester abortion

It is recommended to start taking tablets immediately after a first-trimester abortion. In this case, additional contraceptive methods are not required.

After childbirth or second-trimester abortion

It is advisable to start taking the tablets on days 21–28 after childbirth or second-trimester termination of pregnancy. Women who start taking the tablets later should additionally use barrier methods of contraception for the first 7 days of tablet intake. If unprotected sexual intercourse occurred before starting the medication, pregnancy must be excluded or the first menstrual bleeding must occur before starting the first tablet of Lactinet®-Richter. For additional information on use during breastfeeding, see section "Use during pregnancy or breastfeeding".

How to start taking Lactinet®-Richter after using other contraceptive methods

Switching from combined hormonal contraceptives (combined oral contraceptives (COCs), contraceptive vaginal rings, or transdermal contraceptive patches)

The woman should start taking Lactinet®-Richter the day after taking the last active tablet of the COC (the last tablet containing active ingredients), or on the day of removal of the contraceptive vaginal ring or transdermal contraceptive patch. In these cases, additional contraceptive methods are not required.

Alternatively, the woman may start taking the tablets no later than the day after the end of the pill-free interval, or after the period of placebo tablets of her previous combined hormonal contraceptive, or after discontinuation of patch or ring use. However, in this case, a barrier method of contraception should be additionally used for the first 7 days of tablet intake.

Switching from progestogen-only contraceptives ("mini-pills", injections, implants), or from an intrauterine system (IUS) releasing progestogen

A woman may switch from "mini-pills" at any time (from an implant or IUS – on the day of removal, from injectable forms – on the day the next scheduled injection is due).

Action to be taken in case of missed dose

Contraceptive protection may be reduced if more than 36 hours have passed between taking two tablets. If less than 12 hours have passed since the missed dose, the woman should take the missed tablet as soon as she remembers, and take the next tablet at the usual time. If more than 12 hours have passed since the missed dose, the woman should use an additional method of contraception for the next 7 days. If tablets were missed during the first week after starting Lactinet®-Richter and the woman had sexual intercourse during the week preceding the missed dose, pregnancy should be considered.

Recommendations in case of gastrointestinal disturbances

In case of severe gastrointestinal disorders, absorption of the active ingredient may be incomplete; therefore, additional contraceptive measures are necessary.

If vomiting occurs within 3–4 hours after taking a tablet, absorption of the drug may not be complete. Since this situation is similar to a missed dose, the instructions for missed tablets described in the section "Action to be taken in case of missed dose" should be followed.

Children

The safety and efficacy of Lactinet®-Richter in adolescents under 18 years of age have not been established. Data on use in this age group are lacking.

Overdose

No reports of serious adverse effects due to overdose have been received. In case of overdose, the following symptoms may occur: nausea, vomiting, and slight vaginal bleeding in young girls. There is no antidote; symptomatic treatment is recommended.

Adverse reactions.

During clinical studies, the most commonly reported adverse reaction was irregular bleeding. Approximately 50% of women using desogestrel 0.075 mg tablets reported acyclic vaginal bleeding. Since desogestrel 0.075 mg tablets, unlike other progestogen-only contraceptives, suppress ovulation in nearly 100% of cycles, irregular bleeding occurs more frequently with this medication compared to other progestogen-only contraceptives. In 20–30% of women, bleeding becomes more frequent, whereas in another 20%, it becomes less frequent or may even cease completely. Vaginal bleeding may also become more prolonged.

After two months of taking the medication, a trend toward less frequent menstruation is observed. Information, counseling, and maintaining a menstrual diary can help women adapt to the new menstrual pattern.

Based on clinical studies of desogestrel 0.075 mg tablets, the most frequently reported adverse reactions (>2.5%) were acne, mood changes, breast tenderness, nausea, and weight gain. Adverse reactions are listed in the table below.

Adverse reactions are classified by frequency of occurrence and by system organ classes: common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (<1/1000), and frequency not known (cannot be estimated from available data).

System organ classes (MedDRA) (MedDRA)	Frequency of adverse reactions
	Common	Uncommon	Rare	Frequency not known
Infections and infestations			Vaginal infection
Immune system disorders				Hypersensitivity reactions, including angioedema and anaphylaxis
Psychiatric disorders	Mood changes, depressed mood, decreased libido
Nervous system disorders	Headache
Eye disorders		Intolerance to contact lenses
Gastrointestinal disorders	Nausea	Vomiting
Skin and subcutaneous tissue disorders	Acne	Alopecia	Rash, urticaria, nodular erythema
Reproductive system and breast disorders	Breast pain, menstrual disorder, amenorrhea	Dysmenorrhea, ovarian cysts
General disorders		Fatigue
Investigations	Weight increased

The following adverse reactions may occur during the use of Lactinet®-Richter: galactorrhea and, rarely, ectopic pregnancy (see section "Special Warnings and Precautions for Use"). Additionally, hereditary angioedema may be exacerbated (see section "Special Warnings and Precautions for Use").

A number of (serious) adverse reactions have been reported in women taking (combined) oral contraceptives. These include venous and arterial thromboembolic events, hormone-dependent neoplasms (e.g., liver tumors, breast cancer), and chloasma; some of these are discussed in detail in the section "Special Warnings and Precautions for Use".

Breakthrough bleeding and/or loss of contraceptive efficacy may occur due to interactions between other medicinal products (microsomal enzyme inducers) and hormonal contraceptives (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Reporting of Suspected Adverse Reactions

It is important to report suspected adverse reactions after the medicinal product has been authorized. This allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system for adverse reactions.

Shelf life. 2 years.

Storage conditions.

This medicinal product does not require special storage temperature conditions.

Store in the original packaging to protect from light and moisture.

Keep this medicine out of the reach and sight of children!

Packaging. 28 film-coated tablets per blister; each blister is placed in a laminated aluminum foil pouch; 1 or 3 laminated pouches, together with a cardboard blister holder and package leaflet, are packed in a cardboard box.

Prescription category. Prescription only.

Manufacturer. Gedeon Richter Plc.

Manufacturer's address and place of business.

H-1103 Budapest, Demrédi út 19-21, Hungary.