Pharmacological properties
Pharmacodynamics. The contraceptive effect of Rigevidon tablets is based on the interaction of various mechanisms, the most important of which are inhibition of ovulation and changes in cervical secretion.
Pharmacokinetics
levonorgestrel
Absorption: When administered orally, levonorgestrel is rapidly and completely absorbed from the gastrointestinal tract. Bioavailability is almost 100% due to the lack of first-pass metabolism.
Distribution: Most of levonorgestrel binds to plasma proteins, mainly albumin and sex hormone binding globulin.
Metabolism: mainly consists of cleavage of the Δ4-3-oxo group and hydroxylation at positions 2α, 1β and 16β, followed by conjugation. Most of the circulating metabolites are sulfates of 3α, 5β-tetrahydro-levonorgestrel. Excretion of the drug occurs mainly in the form of glucuronides. Some amount of the original levonorgestrel also circulates in the form of 17β-sulfate. Metabolic clearance is marked by individual variability, which may partly explain the large differences in levonorgestrel concentrations observed in patients.
Elimination: T½ of levonorgestrel shows individual variability and is approximately 36 hours under conditions of equilibrium concentration of the drug in blood plasma. Levonorgestrel is excreted in the urine (40-68%) and feces (16-48%) in the form of metabolites (sulfate and conjugates with glucuronic acid).
ethinylestradiol
Absorption: Ethinylestradiol is absorbed rapidly and almost completely, Cmax in blood plasma is reached after 1.5 hours. After presystemic conjugation and primary metabolism, bioavailability is 60%. The area under the curve and Cmax may increase slightly over time.
Distribution: Ethinylestradiol is 98% bound to plasma proteins, mainly albumin.
Metabolism: Ethinylestradiol is broken down by presystemic conjugation. It passes through the intestinal wall (first phase of metabolism) and enters the liver, where conjugation occurs (second phase of metabolism). The most important metabolites of the first phase of metabolism are 2-OH-ethinylestradiol and 2-methoxyethinylestradiol. Both ethinylestradiol and the first phase metabolites are excreted as conjugates (sulfates and glucuronides) in the bile and enter the enterohepatic circulation.
Elimination: Ethinylestradiol is eliminated from plasma with a T½ of 29 h on average (26-33 h); plasma clearance varies in the range of 10-30 l/h. Ethinylestradiol conjugates and their metabolites are excreted in urine and feces in a 1:1 ratio.
Indication
Oral contraception.
Application
Method of administration: orally, in the order indicated on the package, at approximately the same time, 1 tablet per day, washed down with a small amount of liquid.
If a woman has not used a contraceptive in the previous cycle, the first tablet is started on the 1st day of menstruation and taken 1 tablet per day for 21 days (preferably at the same time of day). Starting on days 2-7 is also possible, but in the first cycle it is recommended to additionally use non-hormonal methods of contraception (such as condoms or spermicides) during the first 7 days of tablet-taking.
After the 21-day course of taking the drug, a 7-day break is taken, during which bleeding usually occurs (usually on the 2nd or 3rd day). The next pack containing 21 tablets should be started on the 8th day after the 7-day break, even if bleeding has not stopped.
This method of using the drug can be continued as long as pregnancy prevention is desired. With regular use of Rigevidon, the contraceptive effect is maintained even during a 7-day break.
Switching from another hormonal contraceptive (pill, vaginal ring or transdermal patch): Rigevidon should be started the day after taking the last pill of the previous contraceptive (removal of the vaginal ring, transdermal patch), but no later than the day after the tablet-free interval (placebo pill, removal of the vaginal ring, transdermal patch) of the previous contraceptive.
Switching to Rigevidon from a progestogen-only pill (low-dose oral contraceptive, injection, implant or intrauterine device): Switching from a low-dose oral contraceptive can be done on any day of the menstrual cycle (from an implant and an intrauterine device on the day of their removal, from an injection on the day when the next injection would be due). In this case, it is recommended to additionally use a barrier method of contraception during the first 7 days of tablet-taking.
After childbirth or after abortion in the second trimester of pregnancy, taking the drug should be started on the 21st-28th day after childbirth or abortion in the second trimester of pregnancy, since there is a risk of thromboembolic disorders during the postpartum period. If a woman starts taking the pill later, barrier methods of contraception should be used additionally during the first 7 days of taking the drug. However, if sexual intercourse has already taken place, then before starting the use of a combined contraceptive, pregnancy should be excluded or wait until the first menstruation.
Lactation: information on use during breastfeeding is provided in the section Use during pregnancy and breastfeeding.
Missed tablets. If less than 12 hours have passed since the next tablet was due, contraception is not reduced. Women should take the missed tablet as soon as they remember, and the next tablet should be taken at the usual time.
If more than 12 hours have passed since the next pill was due, contraception may be reduced. In this case, two basic rules must be followed:
1. The break in taking pills should never exceed 7 days.
2. To achieve adequate suppression of the hypothalamic-pituitary-ovarian system, continuous tablet intake for 7 days is necessary.
Accordingly, in everyday life, one should be guided by the provisions set out in the recommendations below:
Week 1. The last missed tablet should be taken as soon as the woman remembers, even if this means taking 2 tablets at the same time. Then the tablet-taking continues as usual. In addition, barrier methods of contraception (e.g. condoms) should be used simultaneously for the next 7 days. If sexual intercourse has taken place in the previous 7 days, the possibility of pregnancy should be considered. The more tablets are missed and the closer the missed tablet is to the 7-day tablet-free interval, the higher the risk of pregnancy.
Week 2. The last missed tablet should be taken as soon as the woman remembers, even if she has to take 2 tablets at the same time. Then the tablet-taking continues as usual. If the woman has taken the tablets correctly for the 7 days before the missed tablet, there is no need to use additional contraceptive measures. Otherwise, or if more than one tablet is missed, it is recommended to additionally use a barrier method of contraception for 7 days.
Week 3. The risk of a critical reduction in contraceptive protection is inevitable due to the upcoming 7-day break in taking the drug. However, by adhering to the tablet-taking schedule, a reduction in contraceptive protection can be avoided. If you follow one of the options below, you will not need to use additional contraceptive measures, provided that you have taken the tablets correctly for the 7 days before the missed tablet. If this is not the case, it is recommended to follow the first of the options below and use additional contraceptive methods for the next 7 days.
1. The last missed tablet should be taken as soon as the woman remembers, even if 2 tablets should be taken at the same time. Then the tablet-taking continues as usual. The patient should start taking the tablets from the next package the day after taking the last tablet from the current package, i.e. there should be no break between packages. It is unlikely that the woman will start menstrual-like bleeding before finishing the tablets from the second package, although spotting or breakthrough bleeding may occur.
2. It may also be advised to stop taking the tablets from the current pack. In this case, the patient should take a break in taking the drug for up to 7 days, including the days on which she forgot to take the tablets, and then start taking the tablets from the next pack of the drug.
If a woman misses a pill and then has no menstrual-like bleeding during the tablet-free interval, the possibility of pregnancy should be considered.
Gastrointestinal diseases. In the presence of vomiting or diarrhea, the effectiveness of the drug is reduced due to incomplete absorption of the active ingredients.
If vomiting occurs within 3-4 hours of taking the pill, the woman should follow the advice described in the section “Missed pills”.
If a woman does not want to change her usual pill-taking regimen during diarrhea, she should take an additional pill from another pack for as many days as necessary.
In order to accelerate the onset of menstrual bleeding, the 7-day break in taking the drug is reduced by the desired number of days. The shorter the break in taking the drug, the more likely it is that menstrual-like bleeding will not occur, and breakthrough or spotting bleeding will occur during the use of the next package. It is important to emphasize that the break in taking the drug cannot be extended.
Contraindication
Combined oral contraceptives (COCs) are not recommended for use in the presence of the following diseases and pathological conditions. If such diseases develop when using COCs for the first time, the drug should be discontinued immediately: hypersensitivity to the components of the drug; known or suspected pregnancy; presence or history of arterial or venous thromboembolic diseases (e.g. deep vein thrombosis, pulmonary embolism, cerebrovascular accident, myocardial infarction) in combination with or without risk factors (see special instructions); presence of serious and multiple risk factors for arterial or venous thrombosis (see special instructions); presence in history of precursors of thrombosis (e.g. transient ischemic attack or angina pectoris); cardiovascular diseases (e.g. heart disease, heart valve pathology, arrhythmias); severe hypertension; diabetes mellitus with manifestations of micro- or macroangiopathy; ophthalmological disorders of vascular origin; diagnosed or suspected hormone-dependent malignant tumors of the genital organs and mammary glands; severe liver disease or a history of it, as long as liver function tests are not within normal limits; presence or indication in the history of a liver tumor (benign or malignant); vaginal bleeding of unknown etiology; history of migraine with focal neurological symptoms.
Side effects
At the beginning of the use of the drug Rigevidon very often (1/10) were noted intermenstrual bleeding, nausea, weight gain, pain in the mammary glands, a feeling of their tension, headache. These side effects are temporary and resolve on their own.
By organ system and by frequency of occurrence (often ≥1/100; infrequently ≥1/1000-1/100; rarely 1/1000, very rarely 1/10,000) side effects may be as follows.
Neoplasms benign, malignant and unspecified (including cysts and polyps): uncommon - breast cancer, liver adenoma, hepatocellular carcinoma, cervical cancer.
On the part of the immune system: infrequently - systemic lupus erythematosus; rarely - hypersensitivity reactions.
Metabolic: infrequently - fluid retention, hyperlipidemia.
Mental disorders: often - depressed mood, mood swings, nervousness; infrequently - decreased libido; rarely - increased libido.
From the nervous system: often - headache, increased excitability; infrequently - migraine, chorea.
On the part of the organ of vision: often - visual impairment; rarely - contact lens intolerance.
On the part of the organ of hearing: infrequently - otosclerosis.
From the cardiovascular system: infrequently - hypertension, venous thromboembolism, arterial thromboembolism.
From the gastrointestinal tract: often - nausea, abdominal pain; infrequently - vomiting, diarrhea.
From the liver and biliary tract: infrequently - cholelithiasis; rarely - cholestatic jaundice; very rarely - pancreatitis.
Skin and subcutaneous tissue disorders: common - acne; uncommon - rash, urticaria, chloasma; rare - erythema nodosum, exudative erythema multiforme.
From the reproductive system and mammary glands: often - a feeling of tension in the mammary glands, chest pain, irregular bleeding, amenorrhea, hypomenorrhea; infrequently - breast enlargement; rarely - the appearance of secretion from the mammary glands; vaginal discharge, change in vaginal secretion.
Investigations: often - weight gain; infrequently - changes in plasma lipid levels; rarely - weight loss.
The following side effects (without frequency) have been reported by women who have used birth control pills:
Metabolic: hypercholesterolemia, hypertriglyceridemia.
From the nervous system: dizziness, increased epilepsy.
Vascular: phlebitis.
Skin and subcutaneous tissue disorders: hypertrichosis, seborrhea.
Skeletal muscle and connective tissue disorders: feeling of heaviness.
Description of selected adverse reactions: An increased risk of arterial and venous thrombotic and thromboembolic events, including myocardial infarction, stroke, transient ischemic attack, venous thrombosis, phlebitis and pulmonary embolism, has been observed in women taking COCs and is described in more detail in the section "Special warnings and precautions for use".
The following serious side effects have been reported in women using COCs, as described in the section Special warnings and precautions for use: venous and arterial thromboembolic diseases; hypertension; acute cerebrovascular accident (e.g. transient ischemic attack, ischemic stroke, hemorrhagic stroke); liver tumors (benign and malignant).
There have been reports of the development or exacerbation of the following diseases during pregnancy and when using COCs: Crohn's disease, nonspecific ulcerative colitis, jaundice and / or itching associated with cholestasis; formation of stones in the gallbladder; systemic lupus erythematosus, hemolytic uremic syndrome; Sydenham's chorea; herpes gestationis; hearing loss associated with otosclerosis; sickle cell anemia; impaired renal function; porphyria; cervical cancer; anovulatory cycles; metrorrhagia.
Changes in glucose tolerance and effects on peripheral insulin resistance have been reported in women using COCs (see Precautions).
In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.
Special instructions
Examination and clinical examination with the appointment of a CPC. Before starting or resuming the use of a CPC, it is necessary to collect a complete personal and family history of the patient, conduct a clinical examination and exclude pregnancy. During the examination, it is necessary to identify contraindications (see contraindications) and precautions described in this section. The patient should carefully study the instructions for use of the drug and follow the recommendations presented in it. During the entire period of use of oral contraceptives, a clinical examination should be carried out at least once a year. The frequency and nature of periodic examinations should be determined individually for each patient.
Special warnings. General. Patients should be informed that oral contraceptives do not protect against HIV infection (AIDS) and other sexually transmitted infections.
Smoking increases the risk of serious cardiovascular adverse reactions from COC use. This risk increases with age, depends on the number of cigarettes smoked, and is particularly high in women over 35 years of age. All women using COCs should be strongly advised to quit smoking. Women over 35 years of age should consider using other methods of contraception.
If any of the diseases/risk factors listed below are present, the benefits of COCs and the possible risks of their use should be weighed against the individual woman's own and the respective benefits and risks discussed with her before she decides to use such drugs. At the first appearance, worsening or exacerbation of any of these diseases or risk factors, a doctor should be consulted. The doctor should then decide whether to discontinue COC use.
Circulatory disorders. Epidemiological studies have shown that the incidence of venous thromboembolism in women using low-estrogen oral contraceptives (50 mcg ethinylestradiol) is 20-40 cases per 100,000 women per year, but this risk varies depending on the amount of progestogen. This is equivalent to 5-10 cases per 100,000 women per year for women not using COCs. The use of any combined contraceptive increases the risk of venous thromboembolic diseases compared with these figures in women not using COCs.
The risk of these diseases peaks in the first year of drug use. This increased risk is lower than the risk of venous thromboembolic diseases detected during pregnancy, which is 60 cases per 100,000 pregnancies (1-2% of these cases are fatal).
Overall, the probability of thromboembolic diseases when using oral contraceptives containing levonorgestrel and 30 mcg of ethinylestradiol is 20 cases per 100,000 women per year.
There have been very rare reports of thrombosis in other blood vessels, such as hepatic, mesenteric, renal, retinal veins and arteries, in women taking oral contraceptives. The relationship of these events to the use of hormonal contraceptives has not been proven.
The risk of thromboembolism (arterial and/or venous) and cerebral circulation increases: with age; with a serious family history (for example, a disease of a father or brother, sister at a young age). If there is a congenital predisposition to thromboembolic diseases, it is necessary to consult a specialist before using the drug; with prolonged immobilization, severe operations, operations on the lower extremities, severe injuries. Due to the fact that the risk of thromboembolic diseases increases in the postoperative period, it is suggested to stop using the drug 4 weeks before the operation and start taking it 2 weeks after remobilization of the patient; with smoking (excessive smoking and age, especially over 35 years, are additional risk factors); with impaired fat metabolism (dyslipoproteinemia); with obesity (body mass index 30 kg/m2); with hypertension; with heart valve diseases; with atrial fibrillation; with migraine.
There is no consensus regarding the possible role of varicose veins and superficial thrombophlebitis in the development or progression of venous thrombosis.
Symptoms of venous or arterial thrombotic/thromboembolic diseases, cerebrovascular accidents may include: unusual unilateral pain and/or swelling of the legs; sudden severe chest pain, whether or not it spreads to the left arm; sudden shortness of breath; sudden cough for no apparent reason; any unusual, severe or prolonged headache; sudden partial or complete loss of vision; diplopia; slurred speech or aphasia; vertigo; collapse with or without focal epileptic seizure; weakness or very pronounced numbness that suddenly affects one side or one part of the body; movement disorders; acute abdomen.
In the postpartum period, the increased risk of venous thromboembolism should be taken into account.
Other diseases associated with adverse circulatory system reactions include diabetes mellitus, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis), and sickle cell anemia.
In the event of an increase in the frequency or severity of migraine during the use of oral contraceptives (which may be a precursor or a cerebrovascular event), the drug should be discontinued immediately.
Biochemical factors that may indicate a congenital or acquired predisposition to venous or arterial thrombosis include resistance to activated protein C, factor V Leiden mutation, hyperhomocysteinemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, the presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant), and dyslipoproteinemia.
Tumors. Cervical cancer. Some studies have reported an increased incidence of cervical cancer in women who have used combined oral contraceptives for a long time, but the results are mixed. The development of cervical cancer is influenced by sexual behavior and other factors, such as human papillomavirus, so the relationship between cervical cancer and the use of combined oral contraceptives is ambiguous.
Breast cancer. Epidemiological studies have shown that women who have used COCs have a slightly increased relative risk of developing breast cancer. This increased risk gradually decreases during the 10 years after stopping COC use. Since breast cancer rarely occurs in women under 40 years of age, the increase in the number of cases of breast cancer diagnosed in women who are current or past COC users is small compared with the lifetime risk of developing breast cancer.
Evidence of a causal relationship is not presented in these studies. The increased risk may be due to the earlier diagnosis of breast cancer in women who used COCs, the biological effects of COCs, or a combination of both.
In women who use oral contraceptives, breast cancer is diagnosed at a slightly earlier stage compared to women who have not used COCs.
Liver tumors. Benign and very rarely malignant liver tumors have been observed with long-term use of sex hormones, which in some cases can lead to life-threatening bleeding in the abdominal cavity. If severe acute pain in the upper abdomen, liver enlargement or signs of intraperitoneal bleeding occur, a liver tumor may be suspected. This should be taken into account when establishing a differential diagnosis.
Other conditions: Women with hypertriglyceridemia or a family history of this condition are at increased risk of pancreatitis when using COCs. Women with hyperlipidemia should be closely monitored if they decide to use COCs.
Acute or chronic liver dysfunction may require discontinuation of COC use until liver function tests return to normal. In patients with impaired liver function, the metabolism of steroid hormones may be slowed down.
A slight increase in blood pressure has been reported in many women using COCs, but clinically significant increases have been rare. Only in these rare cases has immediate discontinuation of COC use been justified. If, during COC use in patients with pre-existing hypertension, a persistent increase in blood pressure occurs or if a significant increase in blood pressure does not adequately respond to antihypertensive treatment, COC use should be discontinued. In some cases, COC use can be resumed if normal blood pressure values can be achieved with antihypertensive therapy.
There have been reports of the development or exacerbation of the following diseases during pregnancy and when using COCs: jaundice and/or itching associated with cholestasis; formation of gallstones; porphyria; systemic lupus erythematosus, hemolytic uremic syndrome; Sydenham's chorea; herpes gestationis; hearing loss associated with otosclerosis. However, a causal relationship has not been proven.
In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.
The use of COCs has been associated with the development of Crohn's disease and ulcerative colitis.
In rare cases, chloasma may develop, especially in women with a history of pregnancy spots. Women with a tendency to chloasma should avoid direct sunlight or UV radiation while using COCs.
Women who develop severe depression while using COCs should stop using these drugs and use alternative methods of contraception until the causal relationship of depressive symptoms to COC use has been evaluated. Women with a history of major depressive episodes require close monitoring, and COC use should be discontinued if depressive symptoms recur.
Rigevidon film-coated tablets contain lactose. Women with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Rigevidon film-coated tablets contain sucrose. Women with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Herbal remedies containing St. John's wort (Hypericum perforatum) are not used while taking Rigevidon due to the risk of reducing the concentration of active substances in the blood plasma and reducing the pharmacological effect of Rigevidon (see Interactions with other drugs).
Reduced efficacy. The efficacy of COCs may be reduced in the event of missed tablets, vomiting or diarrhoea (see Method of administration) or due to the use of concomitant medications (see Interactions with other medicinal products).
Reduced cycle control. As with all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. Therefore, any irregular bleeding should only be evaluated after the adaptation period of approximately three cycles has been completed.
If irregular bleeding persists or develops after previous regular cycles, the use of non-hormonal methods and appropriate diagnostic measures are recommended to exclude malignancy or pregnancy.
Some women may not have a withdrawal bleed after a break in taking the pill. If the COC has been used according to the instructions in the section on USE, pregnancy is unlikely. However, if the instructions in the section on USE were not followed before the first missed withdrawal bleed or if two consecutive missed withdrawal bleeds occur, pregnancy should be ruled out before continuing COC use.
Use during pregnancy and breastfeeding. The drug is contraindicated during pregnancy. If pregnancy is detected, the drug should be discontinued immediately.
If a woman becomes pregnant while taking the pills, further use should be stopped immediately.
According to the results of a large number of epidemiological studies, neither an increased risk of developing birth defects in children born to women who used COCs before pregnancy, nor a teratogenic effect with the unintentional use of contraceptive pills in early pregnancy have been found.
Breastfeeding. Hormonal contraceptives can reduce milk production and also pass into breast milk in small amounts, so the use of these drugs during breastfeeding is contraindicated.
Children: The drug is not intended for use in children.
Ability to influence the speed of reaction when driving vehicles or operating other mechanisms. The drug does not affect the abilities required for driving vehicles or operating other mechanisms, but, taking into account some adverse reactions (headache), it may have a minor effect.
Interactions
Interactions between the CPC and other drugs may lead to a decrease in the effectiveness of the contraceptive and/or breakthrough bleeding and/or the ineffectiveness of this contraceptive method, so before use, you should always study the information on the use of the concomitant drug.
Drugs that may affect the effectiveness of COCs. Drug interactions that lead to increased clearance of sex hormones may cause breakthrough bleeding and contraceptive failure. This effect has been observed with hydantoins (e.g. phenytoin), barbiturates, primidone, carbamazepine and rifampicin. Other active substances that may reduce the effectiveness of COCs include oxcarbazepine, topiramate and griseofulvin.
In the case of short-term use of any of these drugs that cause an increase in the activity of liver enzymes, it is recommended to use additional barrier methods of contraception from the moment of starting the use of these drugs, during the entire period of treatment and for 4 weeks after their withdrawal. Women receiving these antibiotics in a short course should temporarily use barrier methods of contraception simultaneously with contraceptive pills, i.e. during the period of use of the concomitant drug and for 7 days after its withdrawal. If the next pack of Rigevidon tablets ends earlier than the period in which the use of additional contraceptives is required, the tablets from the next pack should be started without a break in taking the drug. In this case, withdrawal bleeding should not be expected until the tablets from the second pack are finished. If the patient does not have withdrawal bleeding after finishing taking the tablets from the second pack, she should consult a doctor to exclude pregnancy. In the case of long-term use of these drugs, patients are recommended to use other contraceptives.
It has also been reported that HIV protease (ritonavir) and nucleoside reverse transcriptase inhibitors (nevirapine) and their combinations may increase hepatic metabolism.
Troleandomycin, when used concomitantly with COCs, may increase the risk of intrahepatic cholestasis.
St. John's wort (Hypericum perforatum). Herbal medicines based on St. John's wort (Hypericum perforatum) are not recommended for use with this medicine as this may potentially reduce the contraceptive effect of Rigevidon tablets. There have been reports of breakthrough bleeding and unplanned pregnancy. The reduction in contraceptive effect persists for at least 2 weeks after discontinuation of St. John's wort.
Effects of COCs on other medicinal products. Sex steroid hormones may increase the plasma concentration of ciclosporin, which may lead to toxic effects. Concomitant use of lamotrigine and COCs may result in decreased plasma concentrations of lamotrigine and worsening seizure control in women starting COCs.
Laboratory tests. The use of steroid contraceptives may affect the results of certain laboratory tests, including biochemical indicators of liver, thyroid, adrenal and renal function, the concentration of transport proteins (for example, GCS-globulin and lipid / lipoprotein fraction), indicators of carbohydrate metabolism and indicators of blood coagulation and fibrinolysis. Changes usually do not exceed the laboratory limits of the norm.
Overdose
Symptoms of accidental overdose: severe headache, dyspeptic disorders (nausea, vomiting), vaginal bleeding due to drug withdrawal.
Treatment: the drug is discontinued, treatment is symptomatic. There is no specific antidote.
Storage conditions
At a temperature not exceeding 25 °C.
