Pharmacological properties
Pharmacodynamics. Combined contraceptives block the action of gonadotropins. The primary effect of these drugs is to inhibit ovulation. The drug causes a change in cervical mucus, which makes it difficult for sperm to pass into the uterine cavity and affects the endometrium, thereby reducing the possibility of implantation of a fertilized egg. All this helps to prevent pregnancy.
Pharmacokinetics. Levonorgestrel. Absorption: when taken orally, levonorgestrel is absorbed rapidly and completely in the gastrointestinal tract. Bioavailability is almost 100% due to the lack of first-pass metabolism.
Distribution: Most of the 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 metabolites circulating in the blood are sulfates of 3α, 5-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 characterized 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 at steady state. Levonorgestrel is excreted in the urine (40-68%) and feces (16-48%) in the form of metabolites (sulfate and glucuronic acid conjugates).
Ethinylestradiol. Absorption: Ethinylestradiol is absorbed rapidly and almost completely, C max in blood plasma is reached after 1.5 hours. After presystemic conjugation and metabolism, the absolute bioavailability is 60%. AUC and C max 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: 2-OH-ethinylestradiol and 2-methoxy-ethinylestradiol. 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 average of 29 h (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.
First-time use of the drug. Tri-Regol is used from the 1st day of menstruation, 1 tablet per day for 21 days. Starting on days 2-7 is also possible, but during the first cycle it is recommended to additionally use non-hormonal methods of contraception (such as condoms or spermicides) for the first 7 days of taking the tablets.
Since the composition of the different colored tablets is different, you should take the pink tablets for the first 6 days, the white tablets for the next 5 days, and then the dark yellow tablets for 10 days. The order of taking the different colored tablets is indicated by the numbers and arrows on the package.
After the end of the 21-day course of taking the drug, there is a 7-day break, during which bleeding usually occurs (usually on the 2nd or 3rd day). Regardless of whether bleeding occurs or not, and regardless of its duration on the first day after the 7-day break, if further prevention is necessary, the 21-day course of taking Tri-Regol should be started again. With regular use of Tri-Regol, the contraceptive effect is maintained during the 7-day break.
Take Tri-Regol according to the indicated regimen as long as pregnancy prevention is desired.
Switching to Tri-Regol from another oral contraceptive: taking the first Tri-Regol tablet should be started the day after taking the last active (hormone-containing) tablet from the blister pack of the previous contraceptive - no later than 1 day after the usual break in using the previous combined hormonal contraceptive (or after taking the last placebo tablet from the previous package).
Switching to Tri-Regol from a progestogen-only pill (low-dose oral contraceptive, injection, implant or intrauterine contraceptive): Switching from a low-dose oral contraceptive can be done on any day of the menstrual cycle (from an implant and an intrauterine contraceptive on the day after 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 abortion in the second trimester of pregnancy, a woman who is not breastfeeding should start taking the drug 21-28 days after childbirth or abortion in the second trimester of pregnancy. If the start of oral contraception with the use of the drug Tri-Regol occurs later, then it is necessary to additionally use a barrier method of contraception during the first 7 days of taking the tablets.
If sexual intercourse has already taken place, pregnancy must be excluded before starting to take the tablets or taking the tablets should be postponed until the first menstrual bleeding.
Breastfeeding: information on use during breastfeeding is provided in the section “Use during pregnancy and breastfeeding”.
Missed pills: If a woman has missed a pill for any reason, she should take it within 12 hours. In this case, there is no need to use additional contraceptive methods. The remaining pills should be taken at the usual time.
If more than 12 hours have passed, you should take the last missed tablet as soon as you remember, even if you have to take two tablets in one day. Then continue taking the drug as usual. In this case, you should use additional non-hormonal methods of contraception (barrier methods, spermicides) for the next 7 days.
If there are fewer than 7 tablets left in the current pack, you should start taking the tablets from the next pack immediately after taking the last tablet from the current pack; this means that there should be no break between packs. In this case, withdrawal bleeding is not expected until the end of the second pack; however, spotting and breakthrough bleeding may occur.
If withdrawal bleeding has not occurred after the end of the second pack, the possibility of pregnancy should be considered before resuming tablet-taking from the next pack.
Gastrointestinal diseases: in the presence of vomiting or diarrhea, the effectiveness of the drug is reduced due to incomplete absorption of the active substances. Additional non-hormonal methods of contraception (barrier methods, spermicides) should be used while symptoms are present and for the next 7 days to prevent premature bleeding.
If vomiting or acute diarrhea develops within 3-4 hours after taking the tablet, use the recommendations described in the "Missed Tablets" section.
How to delay menstrual bleeding. To delay menstrual bleeding, take Tri-Regol tablets from a new package with dark yellow tablets (the last phase) the day after the end of the current package, without a break between them. The duration of the delay in menstrual bleeding depends on the number of dark yellow tablets taken from the second package. During this period, breakthrough bleeding or spotting may occur. Regular intake of Tri-Regol can be resumed after the usual 7-day break.
Contraindication
Combined oral contraceptives (COCs) are not recommended for use in the presence of the following diseases and pathological conditions. If such diseases develop during the use of COCs, the drug should be discontinued immediately: pregnancy or suspected pregnancy, breastfeeding; hypersensitivity to the components of the drug; presence or history of arterial or venous thromboembolic diseases (e.g. deep vein thrombophlebitis, pulmonary embolism) in combination with or without risk factors (see special instructions); presence of a risk of arterial or venous thromboembolism (blood clotting disorders, heart disease, atrial fibrillation, cerebrovascular disorders, myocardial infarction); presence in history of prodromal symptoms of thrombosis (transient ischemic attacks, angina pectoris); presence or history of cerebrovascular disorders; severe or multiple risk factors for venous or arterial thrombosis may now be considered a contraindication (see special instructions); cardiovascular disease (heart disease, heart rhythm disorders, heart valve pathology); severe AG; diabetes mellitus with vascular disorders; ophthalmological disorders of vascular origin; severe liver disease in history, until liver function tests return to normal; presence or indication in history of liver tumors (benign or malignant); history of migraine with focal neurological symptoms; diagnosed or suspected malignant tumors that are caused by sex steroids (for example, genitals or mammary glands); vaginal bleeding of unknown etiology.
Side effects
By organ system and by frequency of occurrence (very common ≥1/10, common ≥1/100-1/10; uncommon ≥1/1000-1/100, rare ≥1/10,000-1/1000; very rare 1/10,000) side effects may be as follows.
Infections and parasitic diseases: often - vaginitis, candidiasis.
Neoplasms benign, malignant and unspecified (including cysts and polyps): uncommon - breast cancer; very rare - hepatocellular carcinoma, liver adenoma.
Metabolic: often - fluid retention; infrequently - increased or decreased appetite; rarely - decreased glucose tolerance, hyperlipidemia, hypertriglyceridemia; very rarely - exacerbation of porphyria.
Mental disorders: often - mood changes, depression, depressed mood; infrequently - decreased or increased libido, nervousness.
From the nervous system: very often - headache, migraine; often - increased excitability, dizziness; very rarely - exacerbation of chorea, acute cerebrovascular accident.
On the part of the organ of vision: rarely - contact lens intolerance; very rarely - optic neuritis *, retinal artery thrombosis, visual impairment.
On the part of the organ of hearing: rarely - otosclerosis.
Vascular disorders: infrequently - hypertension; rarely - thrombosis, embolism; very rarely - worsening of varicose veins, myocardial infarction.
From the digestive system: often - nausea, vomiting, pain in the stomach; infrequently - stomach cramps, flatulence, diarrhea; very rarely - pancreatitis.
From the liver and biliary tract: rarely - cholestatic jaundice; very rarely - gallbladder disorders, cholelithiasis **.
Skin and subcutaneous tissue disorders: common - acne; uncommon - skin rash, urticaria, chloasma (melasma), hirsutism, alopecia; rare - erythema nodosum, exudative erythema multiforme.
From the kidneys and urinary tract: very rarely - hemolytic-uremic syndrome.
From the reproductive system and mammary glands: very often - breakthrough bleeding, spotting between menstruation; often - chest pain, pain in the mammary glands, engorgement of the mammary glands, the appearance of secretion from the mammary glands, dysmenorrhea, menstrual changes, changes in erosions and secretions from the cervix, amenorrhea; rarely - vaginal discharge.
Investigations: common: change in cervical secretion, weight gain or loss; rare: decreased folate levels ***.
* Optic neuritis can lead to partial or complete loss of vision.
** COC use may worsen existing gallbladder disease and accelerate the development of this disease in women who have not previously had symptoms.
*** The use of COCs may lead to a decrease in plasma folate levels.
The following side effects (without frequency) have been reported by women who have used birth control pills:
Metabolic: hypercholesterolemia.
Mental disorders: irritability.
From the nervous system: cerebrovascular disorders.
Vascular: phlebitis.
Skin and subcutaneous tissue disorders: hypertrichosis, seborrhea.
Skeletal muscle and connective tissue disorders: feeling of heaviness.
From the reproductive system and mammary glands: anovulatory cycles, oligomenorrhea, metrorrhagia, mammary gland disorders.
The following serious adverse reactions have been reported in women using COCs, detailed information on which is provided in the section Special warnings and precautions for use: venous and arterial thromboembolic complications; hypertension; liver tumors; diseases that may develop or worsen with COC use, although the evidence for this fact is inconclusive, include Crohn's disease, ulcerative colitis, epilepsy, migraine, endometriosis, uterine fibroids, porphyria, systemic lupus erythematosus, herpes gestationis, chorea minor; hearing loss associated with otosclerosis; hemolytic-uremic syndrome, cholestatic jaundice; chloasma; acute and chronic liver disorders may require discontinuation of COC use until liver function returns to normal.
The frequency of breast cancer diagnosis is slightly higher among women who use COCs. Since breast cancer is rarely diagnosed in women under 40 years of age, the excess number of breast cancer diagnoses in women who are taking or have recently taken COCs is small compared to the overall risk of developing breast cancer. A causal relationship with COCs has not been established. For more detailed information, see sections 4.3 and 4.4.
In women with hereditary angioedema, the use of estrogens may induce or exacerbate symptoms of angioedema.
Special instructions
Medical examination/consultation. Before starting or re-prescribing the drug, a detailed family history should be taken and a general medical and gynecological examination should be performed (primarily measurement of the blood pressure, determination of blood and urine glucose levels, liver function tests, breast examination, cytological smear analysis) to exclude risk-related diseases and pregnancy. The frequency and nature of the examinations should be based on established clinical guidelines, considering each case individually.
The woman should be warned that the drug does not protect her from sexually transmitted infections, including AIDS.
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 below 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.
Epidemiological studies have also associated COC use with an increased risk of myocardial infarction, transient ischemic attack, and stroke.
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 smoking (excessive smoking and age, especially over 35 years, are additional risk factors); with a serious family history (for example, a father or brother or sister's disease 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 obesity (body mass index 30 kg/m2); with impaired fat metabolism (dyslipoproteinemia); with hypertension; with migraine; with heart valve diseases; with atrial fibrillation; with prolonged immobilization, major operations, operations on the lower extremities, serious injuries. Due to the fact that the risk of thromboembolic diseases increases in the postoperative period, it is proposed to stop taking the drug 4 weeks before the operation and start taking it 2 weeks after the patient's remobilization; 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 or symptoms of cerebrovascular accident 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 without apparent cause; 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.
COC use in general has been associated with an increased risk of acute myocardial infarction or stroke. The mechanisms by which Tri-Regol affects the risk of acute myocardial infarction have not been studied.
In the postpartum period, the increased risk of venous thromboembolism should be taken into account (see Use during pregnancy and breastfeeding).
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.
Tumors. 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. Sexual behavior and other factors, such as human papillomavirus, play a role in the development of cervical cancer, so the relationship between cervical cancer and the use of combined oral contraceptives is ambiguous.
The results of 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 within 10 years after stopping COC use. Since breast cancer is rarely diagnosed 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.
With prolonged use of sex hormones, benign, very rarely malignant liver tumors have been observed, which in some cases can lead to life-threatening bleeding in the abdominal cavity. If severe acute pain appears in the upper abdomen, liver enlargement or signs of intraperitoneal bleeding appear, a liver tumor may be suspected. This must be taken into account when establishing a differential diagnosis.
Other diseases: Women with hypertriglyceridemia or a family history of this disease are at increased risk of pancreatitis when using COCs. Women with hyperlipidemia should be closely monitored if they decide to use COCs.
A slight increase in blood pressure has been reported in many women taking 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.
Although the evidence of an association with COC use is inconclusive, the following conditions have been reported to develop or worsen during pregnancy and COC use: jaundice and/or pruritus associated with cholestasis; gallstone formation; porphyria; systemic lupus erythematosus, hemolytic uremic syndrome; Sydenham's chorea; herpes gestationis; hearing loss associated with otosclerosis.
In women with hereditary angioedema, estrogen administration may induce or exacerbate symptoms of angioedema.
Acute or chronic liver dysfunction may require discontinuation of COCs until liver function tests return to normal. Recurrence of cholestatic jaundice and/or pruritus that occurred during pregnancy or previous use of sex steroids requires discontinuation of COCs.
Although COCs may affect peripheral insulin resistance and glucose tolerance, there is no evidence that a change in the dosage regimen is necessary for diabetic patients taking COCs. However, women with diabetes should be closely monitored while taking COCs.
The development of Crohn's disease and ulcerative colitis is associated with the use of COCs.
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 taking COCs should stop taking 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.
Reduced efficacy. The efficacy of COCs may be reduced if a pill is missed, vomiting or diarrhoea occurs (see Method of administration) or due to concomitant medication (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 an adaptation period of approximately three cycles has been completed.
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 to take the COC.
This medicine contains lactose and sucrose, so it should not be used in case of hereditary intolerance to galactose, lactose, glucose-galactose malabsorption or sucrase-isomaltase insufficiency and in case of fructose intolerance.
Use during pregnancy and breastfeeding. 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 when taking birth control pills unintentionally in early pregnancy has been identified.
Breastfeeding. Hormonal contraceptives can reduce secretion and change the composition of milk, and also penetrate into breast milk in small amounts, so taking these drugs during breastfeeding is contraindicated.
Children: The drug is not intended for use in children.
Ability to influence the reaction speed when driving vehicles or other mechanisms. The drug does not affect the abilities required to drive vehicles or other mechanisms.
Interactions
Interactions between the COC and other drugs may lead to a decrease in the effectiveness of the contraceptive and/or breakthrough bleeding and/or ineffectiveness of this contraceptive method.
Women taking any of these drugs are advised to temporarily use a barrier or other method of contraception in addition to the COC. When taking drugs that induce liver enzymes, a barrier method is required for the entire course of treatment with such drugs and for 28 days after its completion.
Women taking antibiotics (except rifampicin and griseofulvin) are recommended to use a barrier method during antibiotic treatment and for 7 days after its completion.
If concomitant medication continues after the end of the tablet-taking period, the next pack of COCs should be started without the usual break.
Hepatic metabolism: Interactions may occur with medicinal products that induce microsomal enzymes, increasing the clearance of sex hormones (e.g. phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and medicinal products containing St. John's wort (Hypericum perforatum)).
In addition, there have been reports that HIV protease inhibitors (e.g. ritonavir) and non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine), as well as their combinations, may increase hepatic metabolism.
Enterohepatic recirculation: There is information that enterohepatic recirculation of estrogens may increase when certain antibiotics (e.g. penicillin, tetracycline) are prescribed as concomitant medications, which may lead to a decrease in the concentration of ethinylestradiol in the blood plasma.
Troleandomycin may increase the risk of intrahepatic cholestasis when used concomitantly with COCs.
The mechanism of action is based on the ability of these substances to increase the activity of liver enzymes. Maximum enzyme induction is usually observed no earlier than 2-3 weeks after the start of the use of these drugs, but can persist for at least 4 weeks after their withdrawal. Cases of contraceptive failure have also been observed with the simultaneous use of antibiotics such as ampicillin and tetracycline, but the mechanism of action remains unknown.
Herbal medicines based on St. John's wort (Hypericum perforatum) are not recommended for use simultaneously with these drugs, as this leads to a potential reduction in the contraceptive effect of Tri-Regol 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 treatment.
There have been reports of increased plasma concentrations of cyclosporine with concomitant use of COCs. COCs have been shown to induce the metabolism of lamotrigine, resulting in subtherapeutic plasma concentrations of lamotrigine.
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, plasma protein levels, such as corticosteroid-binding globulin and lipid/lipoprotein fractions; indicators of carbohydrate metabolism and indicators of blood coagulation and fibrinolysis. Changes usually do not exceed the laboratory limits of normal.
Overdose
Symptoms of accidental overdose: severe headache, dyspeptic disorders (nausea, vomiting), vaginal bleeding due to drug withdrawal.
Treatment: the drug is canceled, treatment is symptomatic. There is no specific antidote. If the overdose is detected within 2-3 hours and it is significant, gastric lavage may be performed.
Storage conditions
At a temperature not exceeding 25 °C.
