Rigevidone

Rigevidone is a combined oral contraceptive (COC) containing ethinylestradiol and levonorgestrel.

Indications Rigevidon

Oral contraception.

The decision to prescribe Rigevidon should be based on a woman's current individual risk factors, including risk factors for venous thromboembolism (VTE) and the risk of VTE associated with Rigevidon compared to other combined hormonal contraceptives (CHCs) (see Contraindications and Particulars of Use).

Release form

Active ingredients: levonorgestrel, ethinylestradiol;

1 coated tablet contains levonorgestrel 0.15 mg and ethinylestradiol 0.03 mg; other ingredients: anhydrous colloidal silicon dioxide, magnesium stearate, talc, corn starch, lactose monohydrate, sodium carmelose, povidone K-30, polyethylene glycol (macrogol 6000), copovidone, titanium dioxide (E 1).

Coated tablets.

Main physico-chemical properties: white, round, biconvex, coated tablets, 6 mm in diameter.

Pharmacodynamics

Combined estrogen-progestagen birth control pills (minipills).

Perl index: 0.1 per 100 female-years.

The efficacy of CRP is due to a decrease in the secretion of gonadotropins, which leads to suppression of ovarian activity. The resulting contraceptive effect is based on the interaction of various mechanisms, the most important of which is the inhibition of ovulation.

Pharmacokinetics

Ethinylestradiol

Absorption

After oral administration, ethinylestradiol is rapidly and completely absorbed from the gastrointestinal tract, maximum plasma concentration (C max ) is reached in 60 to 180 minutes. After presystemic conjugation and primary metabolism, absolute bioavailability is 40 to 45%. The area under the curve (AUC) and Cmax may increase slightly over time.

Distribution

Ethinylestradiol is 98.8% bound to plasma proteins, almost completely to albumin.

Biotransformation

Ethinylestradiol undergoes presystemic conjugation in the mucosa of the small intestine and in the liver. Hydrolysis of direct conjugates of ethinylestradiol by intestinal flora produces ethinylestradiol again, which can be re-absorbed, thus closing the circle of enterohepatic circulation.The main pathway of ethinylestradiol metabolism is cytochrome P450-mediated hydroxylation, resulting in the formation of the main metabolites, 2-OH-ethinylestradiol and 2-methoxyethinylestradiol. 2-OH-ethinylestradiol is further metabolized to chemically active metabolites.

Conclusion

The elimination half-life (T½) of ethinylestradiol from plasma is approximately 29 hours (26-33 hours); Plasma clearance varies between 10-30 L/hour. Excretion of ethinylestradiol conjugates and its metabolites is 40% with urine and 60% with feces.

Levonorgestrel

Absorption

After oral administration Levonorgestrel is rapidly and completely absorbed from the gastrointestinal tract. Levonorgestrel is completely bioavailable. After oral administration C max of levonorgestrel in plasma is reached in 30-120 minutes. T½ is approximately 24-55 hours.

Distribution

Levonorgestrel binds to albumin and sex hormone binding globulin (GSH).

Biotransformation

It is mainly metabolized by cycle reduction followed by glucuronidation. Metabolic clearance exhibits considerable individual variability, which may partially explain the significant differences in levonorgestrel concentrations observed in female patients.

Conclusion

The T½ of levonorgestrel is approximately 36 h. Approximately 60% of levonorgestrel is excreted with urine and 40% with feces.

Dosing and administration

How to take Rigevidone

Internally, in the order given on the package, at about the same time, taking a small amount of liquid as needed.

Rigevidon should be used daily 1 tablet per day for 21 days. Each subsequent pack is started after a 7-day break, during which menstrual-like bleeding usually occurs (it usually starts on the 2-3rd day after taking the last tablet and may not end until the beginning of the next pack).

How to start using the drug Rigevidon

If no hormonal contraceptives were used in the previous month

You should start taking the pills on day 1 of the natural cycle, which is the first day of menstrual bleeding.

Transitioning from another CGC (CGC, vaginal ring, or transdermal patch)

Rigevidone should be started the day after taking the last active pill of the previous contraceptive, but no later than the day after a break in taking pills of the previous contraceptive.

The first tablet of the drug should be taken on the day of removal of the vaginal ring or transdermal patch, but not later than the day when a new transdermal patch is to be applied or a new ring is to be inserted.

Switching to Rigevidone from a progestogen-only product (progestogen-only pill or minipill, injection, implant, or intrauterine system with progestogen)

Switching from a minipill can be done on any day of the menstrual cycle. Rigevidon should be started the day after stopping the minipill.

Transition from the implant and intrauterine system - on the day they are removed from the injection - on the day the next injection is due.

In all cases, it is recommended that an additional method of contraception be used during the first 7 days of taking the pill.

After an abortion in the first trimester of pregnancy

The use of the drug should be started immediately on the same day after surgery. In this case, there is no need to use additional contraception.

After childbirth or after abortion in the II trimester of pregnancy

Rigevidon should be started from 21-28th day after childbirth and when breastfeeding or abortion in the III trimester of pregnancy is refused, because the risk of thromboembolic disorders during the postpartum period increases. If a woman starts taking Rigevidon later, she should additionally use barrier methods of contraception during the first 7 days of the drug use. However, if sexual intercourse has already taken place, before starting the drug use it is necessary to exclude possible pregnancy or wait until the first day of pregnancy.

Breastfeeding period

See Use during pregnancy or lactation.

What to do if you miss a pill

Contraceptive efficacy may be reduced if pills are missed, especially if the time between the last pill of the current blister pack and the first pill of the next pack is increased.

If less than 12 hours have elapsed since the next pill was due, contraceptive protection is not reduced. A woman should take the missed pill as soon as she remembers it, and the next pill should be taken at the usual time.

If more than 12 hours have elapsed since the next pill was due, contraceptive protection may be reduced. In this case, two basic rules should be followed:

1. A break in taking the tablets can never be more than 7 days.

2. Adequate suppression of the hypothalamic-pituitary-ovarian system is achieved by taking the tablets continuously for 7 days.

According to the above, the following recommendations should be followed in daily life:

Week 1

The last missed pill should be taken as soon as the woman remembers to take it, even if 2 pills have to be taken at the same time. Thereafter, the pill regimen continues as usual. In addition, barrier methods of contraception (e.g. Condom) should be used for the next 7 days.If sexual intercourse has taken place during the previous 7 days, the possibility of pregnancy should be considered. The more pills are missed and the closer the missed pill is to the 7-day break in use, the higher the risk of pregnancy.

Week 2

The last missed pill should be taken immediately after the woman mentions it, even if she has to take 2 pills at the same time. Thereafter, the pill regimen continues as usual. If the woman took the pills correctly for 7 days before missing the first pill, there is no need to use additional contraception. Otherwise, or if more than one pill is missed, it is recommended to use an additional barrier method of contraception for 7 days.

Week 3

The risk of a critical reduction in contraceptive protection is unavoidable due to the upcoming 7-day interruption in use. However, if the pill regimen is followed, a reduction in contraceptive protection can be avoided. If one of the following options is followed, there will be no need to use additional contraceptive methods if the pills are taken correctly within the 7 days before skipping. If this is not the case, it is recommended to follow the first of the suggested options and use additional barrier methods.

1. The last missed pill should be taken as soon as the woman mentions it, even if 2 pills are to be taken at the same time. The next pack of pills should be started the day after the last pill of the current pack, i.e. There should be no pause between packs.It is unlikely that a woman will experience menstrual bleeding before completing the second pack, although she may experience ointment or breakthrough bleeding.

2. A woman may be advised to stop taking the current pack of pills, in which case she should take a break in use for up to 7 days, including the days on which she forgot to take the pills, and then start taking pills from the next pack of pills.

If a woman misses a pill and then does not have menstrual-like bleeding during the first usual break in the use of the drug, the possibility of pregnancy should be considered.

Recommendations in case of gastrointestinal disorders

In case of severe gastrointestinal disorders (vomiting or diarrhea) incomplete absorption of the drug is possible, therefore, it is necessary to use additional contraceptives. If vomiting or severe diarrhea occurs within 3-4 hours after taking the tablet, a new tablet should be taken as soon as possible.If possible, a new tablet should be taken no later than 12 hours after the usual time of taking the tablet. If more than 12 hours have passed, it is necessary to follow the rules for taking the drug as described in the section "What to do if you miss a pill".

If a woman does not want to change her usual drug regimen, she should take an additional tablet(s) from another package.

How to shift the time of menstruation or delay menstruation

To delay menstrual bleeding, taking Rigevidon tablets from a new pack should be started the day after the end of the current pack, with no pause in between. Breakthrough bleeding or ointmental discharge may occur during this period. Regular use of Rigevidon can be restored after the usual 7-day break.

To shift the time of menstrual onset to another day of the week, the 7-day break in the use of the drug is shortened by the desired number of days.

The shorter the break in the use of the drug, the more likely it is that menstrual-like bleeding will not occur, and breakthrough or smeary bleeding will appear when taking tablets from the next package (as in the case of delayed menstruation). It is important to emphasize that the break in the use of the drug should not be increased.

Method of application

Oral.

Kids.

The drug is not intended to be taken by children.

Use Rigevidon during pregnancy

Pregnancy

Rigevidone is not indicated for use during pregnancy.

If a woman becomes pregnant while using Rigevidon, further use should be stopped immediately.

The results of a large number of epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used PDA before pregnancy, nor teratogenic effect in case of inadvertent use of contraceptive pills in early pregnancy. When reinstating the use of Rigevidon, the increased risk of VTE in the postpartum period should be taken into account (see sections "Administration details" and "Administration and dosage").

Breastfeeding period

Oral hormonal contraceptives may affect lactation as they may reduce the amount and change the composition of breast milk. Therefore, the use of PDAs is not recommended until breastfeeding has stopped. Small amounts of contraceptive steroids and/or metabolites may pass into breast milk. These amounts may affect the baby. If a woman wishes to breastfeed, she should be offered other means of contraception.

Contraindications

Combined hormonal contraceptives (CHCs) should not be used if you have any of the following conditions. If any of the following conditions occur for the first time while using combined oral contraceptives, you should stop taking oral contraceptives immediately:

• The presence or risk of venous thromboembolism (VTE):
• venous thromboembolism - existing VTE, particularly due to anticoagulant therapy, or a history of VTE (e.g., deep vein thrombosis (DVT) or pulmonary embolism (PE));
• known inherited or acquired predisposition to VTE, such as resistance to activated protein C (including factor V Leiden mutation), antithrombin III deficiency, protein C deficiency, protein S deficiency;
• major surgical intervention with prolonged immobilization (see section "Application specifics");
• high risk of VTE due to the presence of multiple risk factors (see section "Administration details");
• The presence or risk of arterial thromboembolism (ATE):
• ATE - the presence of a current history of arterial thromboembolism (e.g., myocardial infarction) or a prodromal state (e.g., angina pectoris);
• cerebral circulatory disorder - current stroke, history of stroke, or presence of a prodromal state (e.g., transient ischemic attack (TIA));
• known hereditary or acquired predisposition to develop ATE, such as hyperhomocysteinemia and the presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
• migraine with a history of focal neurologic symptoms;
• high risk of ATE due to the presence of multiple risk factors (see section "Particulars of Use") or due to one of the following serious risk factors:
• Diabetes mellitus with vascular complications;
• severe arterial hypertension;
• severe dyslipoproteinemia;
• current or history of pancreatitis associated with severe hypertriglyceridemia;
• the presence of severe liver disease now or in the history until liver function values return to normal;
• presence or history of liver tumors (benign or malignant);
• diagnosed or suspected hormone-dependent malignancies (e.g., genital or breast);
• vaginal bleeding of unclear etiology;
• hypersensitivity to the active ingredients (levonorgestrel, ethinylestradiol) or to any excipient of the drug (see section "Composition");
• Rigevidon is contraindicated in combination with Hypericum perforatum (see section "Interaction with other medicinal products and other types of interactions").

Rigevidone is contraindicated for concomitant use with medicinal products containing ombitasvir/paritaprevir/ritonavir, dasabuvir, glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir (see sections "Interaction with other medicinal products and other types of interactions").

Side effects Rigevidon

The following adverse reactions have been reported with concomitant use of ethinylestradiol and levonorgestrel.

The most serious side effects, such as venous and arterial thromboembolism, cervical cancer, breast cancer, and hepatic malignancies, are described in the "Particulars of Use" section.

An increased risk of arterial or venous thrombotic and thromboembolic complications, including myocardial infarction, stroke, TIA, venous thrombosis, and TELA, has been observed in women taking CGC. For more information, see the section "Particulars of Use".

System class Bodies	Parts (≥1/100, <1/10)	Infrequent (≥1/1000, <1/100)	Singular (≥1/10000, <1/1000)	Rare (<1/10,000)	Frequency unknown (cannot be determined from available data)
Infectious and parasitic diseases	Vaginitis, including vaginal candidiasis
Benign, malignant and unspecified neoplasms (including cysts and polyps)				Hepatocellular carcinoma, benign liver tumors (focal nodular hyperplasia, liver adenoma)
Immune system disorders			Hypersensitivity, anaphylactic reactions with very rare cases of urticaria, angiodema, circulatory disturbances and severe respiratory disturbances.	Systemic lupus erythematosus exacerbation	Worsening of symptoms of hereditary and acquired angioedema
Metabolic and nutritional disorders		Changes in appetite (increase or decrease)	Glucose tolerance disorder	Porphyria exacerbation
Mental disorders	Mood changes, including depression, changes in libido
Nervous system disorders	Headache, hyperexcitability, dizziness.	Migraine		An exacerbation of chorea
Visual disorders			Contact lens intolerance	Optic neuritis, retinal vascular thrombosis.
Vascular disorders		Arterial hypertension	Venous thromboembolism (VTE), arterial thromboembolism (ATE)	Worsening of varicose veins
Gastrointestinal disorders	Nausea, vomiting, abdominal pain.	Diarrhea, abdominal cramps, abdominal bloating		Ischemic colitis	Inflammatory bowel disease (Crohn's disease, ulcerative colitis)
Liver and biliary tract disorders			Cholestatic jaundice	Pancreatitis, gallbladder stones, cholestasis	Damage to liver cells (e.g, Hepatitis, liver dysfunction)
Disorders of the skin and subcutaneous tissue	Acne	Rash, urticaria, chloasma (melanoderma) with risk of persistence, hirsutism, hair loss	Erythema nodosum	Erythema multiforme
Kidney and urinary tract disorders				Hemolytic uremic syndrome.
Disorders of the reproductive system and mammary glands	Pain, tightness, swelling and discharge from the mammary glands, dysmenorrhea, menstrual irregularity, cervical ectopia and vaginal discharge, amenorrhea
General disorders	Fluid retention/edema, change in body weight (increase or decrease)
Research		Changes in serum lipid levels, including hypertriglyceridemia		Decrease in serum folate levels

The following serious adverse reactions have been reported in women using PDA, as described in the "Particulars of Use" section:

• venous thromboembolic disorders;
• arterial thromboembolic disorders;
• arterial hypertension;
• liver tumors;
• Crohn's disease, nonspecific ulcerative colitis, porphyria, systemic lupus erythematosus, herpes of pregnancy, Sydenham's chorea, hemolytic uremic syndrome, cholestatic jaundice.

Because breast cancer is rare in women under 40 years of age, the increase in breast cancer diagnoses in women currently or recently using CRP is small relative to the overall risk of breast cancer. The relationship with CPC use is unknown. For more information, see Contraindications and Usage Considerations.

Interactions

Breakthrough bleeding and/or decreased contraceptive effect may occur due to interactions of other drugs (enzyme inducers) with oral contraceptives.

Reporting suspected adverse reactions

Reporting suspected adverse reactions during post-marketing surveillance is very important. This provides an opportunity to monitor the benefit/risk ratio of medicines. Health care providers should report suspected adverse reactions.

Overdose

Symptoms of oral contraceptive overdose have been reported in adults, adolescents, and children younger than 12 years of age.

Symptoms that may occur in overdose: nausea, vomiting, breast pain, dizziness, abdominal pain, drowsiness/weakness, and vaginal bleeding in young girls.

There are no antidotes; treatment should be symptomatic.

Interactions with other drugs

Information regarding the medication used should be consulted to identify potential interactions.

Interactions between combined contraceptives and other substances may result in increased or decreased plasma concentrations of estrogen and gestagen.

Decreased plasma concentrations of estrogen and progestogen may increase the frequency of intermenstrual bleeding and may reduce the effectiveness of combined contraceptives.

Contraindicated combinations

St. John's wort (Hypericum perforatum) preparations

Decreased plasma concentrations of hormonal contraceptives due to the effect of St. John's wort preparations on enzyme induction, with consequent risk of decreased or even no efficacy, which may lead to serious consequences (pregnancy).

Ombitasvir/paritaprevir/ritonavir, dasabuvir; glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir

Increased hepatotoxicity.

Pharmacodynamic interactions

Concomitant use with medicines containing ombitasvir/paritaprevir/ritonavir, dasabuvir, with or without ribavirin, glecaprevir/pibrentasvir, and sofosbuvir/velpatasvir/voxilaprevir may increase the risk of ALT elevation (see Contraindications and Special Features. Therefore, patients taking Rigevidone should switch to an alternative method of contraception (e.g., progestogen-only contraceptives or non-hormonal methods) before starting therapy with the above combination therapies. Rigevidone use can be restored 2 weeks after completion of treatment.

Pharmacokinetic interactions

Effect of other medicines on Rigevidone

Interaction with drugs that induce microsomal enzymes may occur, which may result in increased clearance of sex hormones and may cause breakthrough bleeding and/or loss of contraceptive efficacy.

Therapy

Enzyme induction can be detected as early as a few days of treatment. Maximum enzyme induction is generally observed after a few weeks. After withdrawal of the drug, enzyme induction may take up to 4 weeks.

Short-term treatment

Women taking enzyme-inducing drugs should temporarily use a barrier method or other method of contraception in addition to the CCP. A barrier method of contraception should be used during the entire period of treatment with the respective drug and for 28 days after discontinuation. If therapy with an enzyme-inducing drug continues after the last 21-tablet pack of CCP has been used, the tablets of the subsequent pack of CCP should be started immediately after the last 21-tablet pack without interruption.

Long-term treatment

In women on long-term therapy with active substances that induce liver enzymes, it is recommended to use another reliable non-hormonal method of contraception.

The following interactions were recorded according to published data.

Actives that increase the clearance of CRP (decrease the effectiveness of CRP due to enzyme induction), such as barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin, and HIV medications: ritonavir, nevirapine, and efavirenz; also possibly felbamate, griseofulvin, oxcarbazepine, topiramate, and drugs containing St. John's wort extract ( Hypericum perforatum ).

Active substances with non-permanent effects on PDA clearance

A large number of combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with hepatitis C virus (HCV) inhibitors, may increase or decrease plasma concentrations of estrogen or progestins when used concomitantly with CRPC. The combined effect of these changes may be clinically significant in some cases. Therefore, information on the medical use of the drug for the treatment of HIV infection should be consulted for potential interactions and any other recommendations.

Effect of Rigevidon on other medicines

CRPs can affect the metabolism of other drugs. Given this, can alter the plasma and tissue concentrations of active substances - both increasing (e.g., cyclosporine) and decreasing (e.g., lamotrigine).

Unrecommended combinations

Enzyme inducers

Anticonvulsant medications (phenobarbital, phenytoin, fosphenytoin, primidone, carbamazepine, oxacarbazepine), rifabutin, rifampicin, efavirenz, nevirapine, dobrafenib, enzalutamide, eslicarbazepine.

Decreased contraceptive efficacy due to increased hepatic metabolism of hormonal contraceptives by the inducer.

If these drug combinations are used and during the next cycle, another method of contraception, such as mechanical contraception, is recommended.

Lamotrigine (see also "Combinations requiring precautions for use" below)

Risk of decreased concentration and efficacy of lamotrigine due to increased metabolism in the liver.

When adjusting the dose of lamotrigine, the use of oral contraceptives is not recommended.

Protease inhibitors in combination with ritonavir

Amprenavir, atazanavir, daravir, fosamprenavir, indinavir, lopinavir, ritonavir, saquinavir and tipranavir

Risk of decreased contraceptive efficacy due to decreased concentrations of hormonal contraceptives as a result of increased metabolism in the liver by ritonavir.

When using these combinations of medicines and during the next cycle, it is recommended that you use another method of contraception, such as a condom or IUD.

Topiramate

Topiramate 200 mg/day dose: risk of decreased contraceptive efficacy due to decreased estrogen concentration.

Another method of contraception, such as mechanical contraception, is recommended.

Troleandomycin

May increase the risk of intrahepatic cholestasis when used concomitantly with CRP.

Modafinil

There is a risk of decreased contraceptive effect during administration and in the next cycle after discontinuation of modafinil because it is an inducer of microsomal liver enzymes.

Conventional oral contraceptives (not low-dose) or other contraceptive methods should be used.

Vemurafenib

There is a risk of decreased estrogen and progestogen concentrations with a subsequent risk of lack of efficacy.

Perampanel

When using perampanel in a dose equal to or higher than 12 mg per day, there is a risk of decreased contraceptive effect. It is recommended to use other methods of contraception, mainly barrier methods.

Ulipristal

There is a risk of progestogen suppression. Combined contraceptives should not be reinstated sooner than 12 days after discontinuation of ulipristal.

Combinations requiring precautions in use

Bozentan

Risk of decreased contraceptive efficacy due to increased hormonal contraceptive metabolism in the liver.

Use a reliable, supplemental, or alternative method of contraception while using this drug combination and subsequent cycle.

Griseofulvin

Risk of decreased contraceptive efficacy due to increased hormonal contraceptive metabolism in the liver.

It is advisable to use another method of contraception, especially a mechanical method, during the use of this drug combination and subsequent cycle

Lamotrigine

Risk of decreased concentration and efficacy of lamotrigine due to increased metabolism in the liver.

Clinical monitoring and adaptation of lamotrigine dosing at the start of oral contraceptives and after discontinuation.

Rufinamide

Leads to a moderate decrease in ethinyl estradiol concentrations. It is recommended to use other methods of contraception, mainly barrier methods.

Elvitegravir

Ethinyl estradiol concentrations are decreased with a risk of decreased contraceptive efficacy. In addition, there is an increase in progestogen concentrations.

Use a combined contraceptive containing at least 30 mcg of ethinylestradiol.

Apprepitant

Decreased concentrations of combined contraceptives or progestogens with a risk of decreased contraceptive efficacy.

It is preferable to use another method of contraception, especially mechanical contraception, when using this drug combination and subsequent cycle.

Boceprover

Risk of decreased contraceptive efficacy due to increased hepatic metabolism of the hormonal contraceptive by boceprevir.

Use a reliable, additional or alternative method of contraception when using this drug combination.

Telaprever

Risk of decreased contraceptive efficacy due to increased hepatic metabolism of hormonal body contraceptive verified.

Use a reliable, additional or alternative method of contraception when using this drug combination and two subsequent cycles.

Combinations to be used with caution

Etoricoxib

In concomitant use with etoricoxib, an increase in the concentration of ethinyl estradiol is observed.

Laboratory tests

Contraceptive steroid use may affect the results of selected laboratory tests, including biochemical measures of liver, thyroid, adrenal, and renal function, as well as levels of plasma transport proteins such as corticosteroid-binding globulin and lipid fractions; measures of carbohydrate metabolism, coagulation, and fibrinolysis Changes generally occur within the normal range of laboratory values.

Storage conditions

Store at a temperature not exceeding 25 ° C.

Keep the drug out of the reach of children.

Special instructions

If any of the diseases/risk factors listed below are present, the beneficial effects of CPCs and possible risks of their use should be assessed in the individual woman and the associated benefits and risks discussed with her before she decides to use such medications. At the first manifestation, worsening, or exacerbation of any of these diseases or risk factors, the woman should consult her physician. The physician should decide whether to discontinue CPCs.

Circulatory disorders

Risk of venous thromboembolism (VTE)

The risk of VTE (e.g. DVT or TELA) is increased with the use of any SCC compared to no use. The use of levonorgestrel, norgestimate or norethisterone-containing products is associated with a lower risk of VTE. The decision to use Rigevidon should be made only after discussion with the woman.It should be ensured that she is aware of the risk of VTE associated with the use of Rigevidone, the extent to which her risk factors influence her risk, and the fact that the risk of VTE is highest during the first year of use. Some evidence suggests that the risk of VTE may increase when the woman regains IUGR after a break of 4 weeks or more.

Among women who do not use CGC and are not pregnant, the incidence of VTE is approximately 2 cases per 10,000 women per year. However, any given woman may be at much higher risk, depending on her underlying risk factors (see below).

It has been found that of 10,000 women using CCPs containing levonorgestrel, approximately 6 1 women will develop VTE within one year.

The number of VTE cases per year is lower than normal expected during pregnancy or postpartum.

VTE can be fatal in 1-2% of cases.

1 An average of 5-7 cases per 10,000 women-years based on a calculation of the relative risk of levonorgestrel-containing CGCs compared with that of women not receiving CGCs (approximately 2.3 to 3.6 cases).

Thrombosis in other blood vessels, such as arteries and veins of the liver, kidney, retina, or mesenteric vessels, has very rarely been reported in women using contraceptive pills.

Risk factors for VTE development

Against the background of CGC use, the risk of venous thromboembolic complications may significantly increase in women with additional risk factors, especially in the presence of multiple risk factors (see Table 1).

The drug Rigevidone is contraindicated in women with multiple risk factors, based on which one can be attributed to a high-risk group for venous thrombosis (see section "Contraindications").If a woman has more than one risk factor, the increase in risk may be greater than the sum of the risks associated with each individual factor, so the overall risk of VTE should be taken into account. CGC should not be prescribed if the benefit/risk ratio is unfavorable (see section "Contraindications").

Table 1

Risk factors for VTE development

Risk factors	Note
Obesity (body mass index (BMI) is greater) 30 kg/m2).	The risk increases significantly with increasing BMI. Particular attention is required when women have other risk factors.
Prolonged immobilization, major surgery, any leg or pelvic surgery, neurosurgery or extensive trauma. Note: Temporary immobilization, including air travel for more than 4 hours, may also be a risk factor for VTE, especially for women with other risk factors.	In such cases, it is recommended to discontinue use of the patch/pill/ring (in case of planned surgical intervention for at least 4 weeks) and not to resume use earlier than 2 weeks after full recovery of motor activity. To avoid unexpected pregnancy, another method of contraception should be used. Consideration should be given to the appropriateness of antithrombotic therapy if Rigevidone has not been discontinued beforehand.
Family history (VTE in a sibling or parents, especially at a relatively young age, e.g. Before age 50).	If a hereditary predisposition is suspected, women are advised to consult a specialist before using any CGC.
Other conditions associated with VTE	Cancer, systemic lupus erythematosus, hemolytic-uremic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis), and sickle cell anemia.
Increase in age	Especially persons aged 35 years and older.

There is no consensus on the possible influence of varicose veins and superficial thrombophlebitis on the development or progression of venous thrombosis.

Attention should be paid to the increased risk of thromboembolism during pregnancy, especially during the first 6 weeks after delivery (see Use during pregnancy or lactation).

Symptoms of VTE (DVT and TELA)

If symptoms occur, a woman should seek immediate medical attention and inform her doctor that she is taking CGC.

Symptoms of deep vein thrombosis (DVT) may include:

• Unilateral swelling of the leg and/or foot or an area along a vein in the leg;
• pain or hypersensitivity in the leg that can only be felt when standing or walking;
• Feeling of heat in the affected leg; redness or discoloration of the skin on the leg.

Symptoms of TELA may include:

• sudden shortness of breath of unclear etiology or rapid breathing;
• A sudden onset of cough that may be accompanied by hemoptysis;
• sudden chest pain;
• fainting or dizziness;
• rapid or irregular heartbeat.

Some of these symptoms (e.g., dyspnea, cough) are nonspecific and may be misdiagnosed as more common or less severe (e.g., respiratory tract infections).

Other signs of vascular occlusion may include sudden pain, swelling, and slight blueing of the limb.

In ocular vascular occlusion, the initial symptomatology may be blurred vision without pain, which may progress to vision loss. Sometimes vision loss develops almost immediately.

Risk of developing ATE

Epidemiologic studies have found that the use of any CCG is associated with an increased risk of ATE (myocardial infarction) or cerebrovascular events (e.g., transient ischemic attack, stroke). Arterial thromboembolic events can be fatal.

Risk factors for the development of ATE

When using CGC, the risk of arterial thromboembolic complications or cerebrovascular events increases in women with risk factors (see Table 2). Rigevidone is contraindicated if a woman has one serious or multiple risk factors for ATE that may increase the risk of arterial thrombosis (see Contraindications). "If a woman has more than one risk factor, the increase in risk may be greater than the sum of the risks associated with each individual factor, so the overall risk of developing ATE should be considered. CGC should not be prescribed if the benefit/risk ratio is unfavorable (see Contraindications).

Table 2

Risk factors for the development of ATE

Risk factors	Note
Increase in age	Especially persons aged 35 years and older.
Smoking	Women who wish to use CGC should be advised to stop smoking. Women 35 years and older who continue to smoke should be strongly advised to use another method of contraception.
Arterial hypertension
Obesity (BMI greater than 30 kg/m2)	The risk increases significantly with increasing BMI. Particular attention is required when women have other risk factors.
Family history (arterial thromboembolism in a sibling or parent, especially at a relatively young age, such as under 50 years of age).	If a hereditary predisposition is suspected, women are advised to consult a specialist before using any CGC.
Migraine	An increase in the incidence or severity of migraine while using CGC (may be a prodromal state prior to the development of cerebrovascular events) may be a reason to discontinue CGC immediately.
Other conditions associated with adverse vascular reactions	Diabetes mellitus, hyperhomocysteinemia, heart valve defects, atrial fibrillation, dyslipoproteinemia, and systemic lupus erythematosus.

Symptoms of ATE

If symptoms occur, a woman should seek immediate medical attention and inform her doctor that she is taking CGC.

Symptoms of a cerebrovascular disorder may include:

• Sudden numbness or weakness of the face, arms, or legs, especially unilateral;
• sudden gait disturbance, dizziness, loss of balance or coordination;
• sudden confusion, impaired speech or comprehension;
• A sudden loss of vision in one or both eyes;
• A sudden severe or prolonged headache with no definite cause;
• loss of consciousness or fainting with or without seizures.

Temporality of symptoms may indicate a transient ischemic attack (TIA).

Symptoms of myocardial infarction (MI) may include:

• pain, discomfort, pressure, heaviness, tightness or tightness in the chest, arm or behind the sternum;
• discomfort with irradiation to the back, jaw, throat, arm, abdomen;
• A feeling of fullness in the stomach, impaired digestion or choking;
• Increased sweating, nausea, vomiting or dizziness;
• extreme weakness, restlessness or shortness of breath;
• rapid or irregular heartbeat.

Tumors

Cervical cancer

Some epidemiologic studies have reported an increased risk of cervical cancer in women who used CRPC for a long time (>5 years), but this claim is still controversial because it is not definitively clarified to what extent the findings account for associated risk factors, such as sexual. Behavior and human papillomavirus (HPV) infection

Breast cancer

A meta-analysis of data from 54 epidemiologic studies indicates a small increase in the relative risk (HR = 1.24) of developing breast cancer in women using CRPS. This increased risk gradually decreases over the 10 years after discontinuation of CRPS. Because breast cancer is rare in women under 40 years of age, the increase in breast cancer diagnoses in women using or recently using CRPS is small compared to the overall risk of breast cancer.Evidence of a causal relationship in these and

The increased risk may be due to earlier diagnosis of breast cancer in women who have used CGC, the biological effects of CGC, or a combination of both. Women who use oral contraceptives are diagnosed with breast cancer at an earlier stage compared to women who have not used CGC.

Liver tumors

In rare cases, benign (adenoma, focal nodular hyperplasia) and even rarer cases - malignant liver tumors have been observed in women taking KGC. In some cases, these tumors may lead to life-threatening intra-abdominal hemorrhages.The presence of a liver tumor should be kept in mind during the differential diagnosis when women using CGC have severe upper abdominal pain, liver enlargement, or signs of intra-abdominal hemorrhage.

High-dose (50 mcg ethinylestradiol) CRP reduces the risk of endometrial and ovarian cancer. It remains to be confirmed whether these findings may apply to low-dose CRP as well.

Other conditions

Depression

Depressed mood and depression are common adverse reactions with hormonal contraceptives (see Adverse Reactions). Depression can be severe and is a known risk factor for suicidal behavior and suicide. Women should be informed to seek medical attention for mood swings and symptoms of depression, even if they occur soon after starting treatment.

Hypertriglyceridemia

Women with hypertriglyceridemia or such a family history of the disease are at increased risk of pancreatitis when using CGC.

Arterial hypertension

Slight increases in BP have been reported in many women using SCC, but clinically significant increases have been rare. Only in these rare cases has immediate discontinuation of SCC been justified. If SCC use with existing hypertension results in persistently elevated BP or if significant increases in BP do not respond adequately to antihypertensive treatment, SCC use should be discontinued. In some cases, SCC use may be reinstated if normal BP values can be achieved with hypo

Liver disease

Acute or chronic liver dysfunction may require discontinuation of CRP until liver function tests return to normal.

Angiodema

Exogenous estrogens can induce or exacerbate symptoms of hereditary and acquired angioedema.

Glucose tolerance/diabetes mellitus

Although CGCs may affect peripheral insulin resistance and glucose tolerance, there is no evidence that the therapeutic dosing regimen should be altered for women with diabetes taking low-dose CGCs (containing <0.05 mg ethinylestradiol). However, women with diabetes should be continuously monitored throughout the duration of CGC use.

Other conditions

In case of recurrence of cholestatic jaundice first occurring during pregnancy or prior use of sex steroid hormones, the use of CGC should be discontinued.

There have been reports of development or exacerbation of such diseases in pregnancy and with the use of KGC (the relationship with the use of KGC has not been clarified): jaundice and/or pruritus associated with cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; Sydenham's chorea; herpes of pregnancy; hearing loss associated with otosclerosis.

Endogenous depression, epilepsy, Crohn's disease, and ulcerative colitis have been observed to worsen with the use of CGC.

Chloasma may occasionally occur, especially in women with a history of pregnancy chloasma. Women with a predisposition to chloasma should avoid direct sunlight or ultraviolet radiation when using CGC.

Special attention should be paid to patients with hyperprolactinemia.

Medical examination/consultation

Before starting or restarting Rigevidone, the patient's medical history, including family history, should be carefully reviewed and pregnancy should be excluded. BP should also be measured and a general examination should be performed, taking into account contraindications (see Contraindications section) and special reservations (see Particulars of Use section).It is important to draw the woman's attention to information on venous and arterial thrombosis, including the risk of using Rigevidone compared to other CGCs, symptoms of VTE and ATE, known risk factors and what to do in case of suspected thrombosis. The instructions for medical use should be read carefully and the recommendations given therein should be followed. The frequency and nature of examinations should be based on current standards of medical practice, taking into account the individual characteristics of each woman.

Be warned that oral contraceptives do not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Reduced efficiency

The efficacy of CRP may be reduced, for example, if you miss taking tablets (see section "Administration and doses"), vomiting, diarrhea (see section "Administration and doses") or if you take other medicines at the same time (see section "Interaction with other medicines and other types of interactions").

Reduced cycle control

As with all PDAs, irregular bleeding (smeary discharge or breakthrough bleeding) may develop, especially in the first few months of use, so any irregular bleeding should be evaluated only after the body has completed the drug adaptation period of approximately three cycles..

If irregular bleeding persists or occurs after several regular cycles, non-hormonal causes should be considered and appropriate diagnostic measures should be taken to rule out malignancy or pregnancy. These measures may include curettage.

Some women may not experience menstrual bleeding during a normal break in the use of a CCP. If CCPs have been used according to the "Directions for Use and Dosage" section, pregnancy is unlikely. However, if the directions in the "Directions for Use and Dosage" section have not been followed before the first absence of withdrawal bleeding, or if menstrual bleeding is absent for two cycles, pregnancy should be ruled out before continuing CCP use.

ALT elevation

During clinical trials with patients receiving medications for the treatment of hepatitis C virus (HCV) infections containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, an increase in transaminase (ALT) levels of more than 5-fold was found during clinical trials. This occurred with significantly greater frequency in women using medications containing ethinylestradiol, such as CGC.Increases in ALT levels have also been observed with antiviral medicines containing glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir (see Contraindications and Drug Interactions and Other Interactions sections).

Auxiliary substances

Rigevidone, coated tablets, contains lactose monohydrate. Women with rare inherited disorders of galactose intolerance, complete lactase deficiency or glucose-galactose malabsorption should not use this medicine.

Rigevidone, coated tablets, contains sucrose. Women with rare hereditary fructose intolerance, glucose and galactose absorption disorders and sugar-isomaltase deficiency should not use this preparation.

Rigevidone, film-coated tablets, contains sodium carmelose.

One coated tablet contains less than 1 mmol (23 mg)/dose of sodium, that is, the drug is virtually sodium free.

Ability to affect reaction speed when driving motor transport or other mechanisms.

No studies of the effect on the ability to drive vehicles and operate other mechanisms have been conducted. In women who used KGC, no effect on the ability to drive motor vehicles and operate mechanisms was observed.

Shelf life

30 months.