Pharmacological properties
Pharmacodynamics. The action of combined oral contraceptives (COCs) is based on the interaction of various factors, the most important of which are the suppression of ovulation and changes in cervical secretion. In addition to preventing pregnancy, COCs have a number of positive properties that may be useful when choosing a contraceptive method. The menstrual cycle becomes more regular, menstruation is less painful, and blood loss is reduced. The latter may contribute to a decrease in the incidence of iron deficiency anemia. There is evidence that the use of high-dose combined contraceptives (50 μg ethinylestradiol) reduces the risk of developing benign breast diseases, ovarian cysts, pelvic inflammatory disease, ectopic pregnancy, endometrial and ovarian cancer.
Pharmacokinetics.
desogestrel
Absorption. Orally administered desogestrel is rapidly and completely absorbed and converted to etonogestrel. C max in blood plasma (about 2 ng / ml) is achieved approximately 1.5 hours after a single dose. Bioavailability is 62-81%.
Distribution. Etonogestrel binds to serum albumin and sex hormone binding globulin (SHBG). Only 2-4% of the total plasma concentration is found as free steroid, and 40-70% is specifically bound to SHBG; the ethinylestradiol-induced increase in SHBG affects the distribution between plasma proteins, leading to an increase in the SHBG-bound fraction and a decrease in the albumin-bound fraction; the estimated volume of distribution of desogestrel is 1.5 l/kg.
Metabolism: Etonogestrel is completely metabolized by known steroid metabolism pathways; metabolic clearance rate from blood is about 2 ml/min/kg body weight; no interaction with co-administered ethinylestradiol has been identified.
Elimination. The level of etonogestrel in the blood decreases in two phases; the distribution in the final phase is characterized by a T ½ of about 30 hours; desogestrel and its metabolites are excreted in urine and bile in a ratio of 6: 4.
The pharmacokinetics of etonogestrel are influenced by the level of GH, which increases threefold under the influence of ethinylestradiol; with daily administration, its serum level increases approximately 2-3-fold, reaching a steady state in the second half of the course of drug use.
ethinylestradiol
Absorption. After oral administration, ethinylestradiol is rapidly and completely absorbed; C max in serum (approximately 80 pg / ml) is achieved within 1-2 hours; absolute bioavailability as a result of presystemic conjugation and first-pass metabolism is about 60%.
Distribution: Ethinylestradiol binds strongly but nonspecifically to serum albumin (almost 98.5%) and causes an increase in serum SHBG concentrations; the volume of distribution is about 5 L/kg.
Metabolism. Ethinylestradiol is subject to presystemic conjugation in both the small intestinal mucosa and the liver; ethinylestradiol is initially metabolized by aromatic hydroxylation, but this produces a large number of hydroxylated and methylated metabolites, which are subsequently present not only as free metabolites, but also as conjugates with glucuronides and sulfates; the metabolic clearance rate is about 5 ml/min/kg.
Excretion. The level of ethinylestradiol in the blood decreases in two phases, the distribution in the final phase is characterized by T ½ about 24 hours. The unchanged active substance is not excreted, the metabolites of ethinylestradiol are excreted with urine and bile in a ratio of 4: 6; T ½ of the metabolites is about 1 day.
Steady state. Steady state concentrations are reached after 3-4 days of taking the drug, when its level in the blood is 30-40% higher compared to taking a single dose.
Indication
Pregnancy prevention (contraception).
Application
General rules for taking Marvelon.
The tablets should be taken daily for 21 days in accordance with the order indicated on the package without interruption, at approximately the same time, one tablet per day, washed down with a small amount of liquid if necessary. After a 21-day course, a break of 7 days is taken. During this period, a menstrual-like reaction occurs, the duration of which may be shorter and the intensity lower than that of normal menstruation. As a rule, it begins on the 2-3rd day after taking the last tablet and can continue until the start of the next course of the drug (the next package). Taking tablets from the next package begins after 7 days of the “pill-free” period.
Starting Marvelon
Hormonal contraceptives were not used in the previous period (last month)
Tablet-taking begins on day 1 of the natural cycle (i.e., the first day of menstrual bleeding). A woman can also start taking it on days 2-5, but in this case, during the first cycle, it is recommended to additionally use a barrier method of contraception for the first 7 days of tablet-taking.
Switching from another PDA
It is advisable for a woman to start taking Marvelon the day after taking the last active tablet of her previous combined contraceptive, but no later than the day after the tablet-free or placebo-free period of her previous combined contraceptive.
A woman can start taking Marvelon any day after stopping the minipill (in the case of an implant - on the day of its removal, in the case of injections - instead of the next injection). However, in all cases it is recommended to additionally use a barrier method of contraception during the first 7 days of tablet-taking.
After an abortion in the first trimester
A woman can start taking Marvelon immediately. In this case, she does not need to use additional methods of contraception.
After childbirth or abortion in the second trimester
Women should be advised to start taking Marvelon on the 21st or 28th day after childbirth or abortion in the second trimester. If the start of taking Marvelon is later, a barrier method of contraception should be used additionally during the first 7 days of taking the tablets. However, if sexual intercourse has already occurred, then before starting the use of the COC, pregnancy should be established or the next menstruation should be waited for.
What to do if you miss a pill
If the delay in taking the tablet did not exceed 12 hours, the contraceptive effect of Marvelon will be maintained throughout the entire period of taking the drug. If for any reason a woman forgets to take a Marvelon tablet, she should take it as soon as she finds out. In the future, taking the tablets from this pack should be continued as usual.
If you are more than 12 hours late taking a pill, the contraceptive effect may be reduced. In case of missing a pill, you can follow 2 basic rules:
taking pills cannot be interrupted for more than 7 days;
To achieve adequate inhibitory effect of the drug on the hypothalamic-pituitary-ovarian axis, continuous administration of the drug for 7 days is necessary.
Accordingly, it is recommended to follow the following advice.
First week
The woman should take the last missed tablet as soon as she remembers, even if this means taking 2 tablets at the same time. She then continues taking the tablets at the usual time. In addition, a barrier method of contraception should be used 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 usual tablet-free period, the higher the risk of pregnancy.
Second week
The woman should take the last missed tablet as soon as she remembers, even if this means taking 2 tablets at the same time. She then continues taking the tablets at the usual time. 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 1 tablet is missed, a barrier method of contraception should be used for 7 days.
third week
The risk of reduced contraceptive reliability increases as the tablet-free interval approaches. However, by adhering to the tablet-taking schedule, a reduction in contraceptive reliability can be avoided. If one of the following rules is followed, there is no need to use additional contraceptive measures, provided that the woman has taken the tablets correctly for the 7 days preceding the missed tablet. If not, the woman should follow the first of the following rules and use additional methods of contraception for the next 7 days.
The woman should take the last missed tablet as soon as she remembers, even if this means taking 2 tablets at the same time. She then continues taking the tablets at the usual time. The tablets from the next pack should be started immediately after the previous one has finished, i.e. there should be no break between taking the tablets from different packs. It is unlikely that the woman will have menstrual-like discharge before finishing the tablets from the second pack, although spotting or breakthrough bleeding may occur during tablet-taking.
The woman may also be advised to stop taking the tablets from the current pack. In this case, the break should be 7 days, including the days of skipping the tablets; taking the tablets should be started from the next pack. If the woman has missed taking the tablets and she does not have menstrual-like discharge during the first usual break in taking the drug, pregnancy should be assumed.
Recommendations in case of vomiting
If vomiting occurs within 3-4 hours after taking the tablet, incomplete absorption of the drug is possible. In this case, it is advisable to follow the recommendations for skipping a tablet. If a woman does not want to change her usual regimen, she should take an additional tablet from another package.
How to change or delay the start of menstruation
In order to change the date of menstruation - to move its onset to another day of the week, a woman may be advised to shorten the tablet-free period by the required number of days. The shorter this period, the greater the likelihood of no withdrawal bleeding and the occurrence of spotting or short-term bleeding during the next pack (as with a delayed period).
Contraindication
The use of combined contraceptives is contraindicated in any of the following conditions. If any of these conditions occur during the first use of combined contraceptives, the drug should be discontinued immediately:
thrombosis (venous or arterial), including the presence of indications in the anamnesis (for example, deep vein thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular disorders);
presence, including a history, of precursors of thrombosis (for example, angina pectoris, cerebrovascular accident);
migraine with focal neurological symptoms;
diabetes mellitus with vascular complications;
the presence of thrombosis;
pancreatitis or past pancreatitis accompanied by high hypertriglyceridemia;
severe liver disease, including the presence of indications in the anamnesis (until normalization of liver function tests);
liver tumors (benign or malignant), including a history;
hormone-dependent malignant tumors (established or suspected, for example, tumors of the genital organs or mammary glands);
vaginal bleeding of unknown etiology;
established or suspected pregnancy;
hypersensitivity to any component of the drug.
COCs should be taken with caution in any of the following conditions: obesity (body mass index 30 kg/m2); high blood pressure; atrial fibrillation; heart valve disease; dyslipoproteinemia; liver and gallbladder disease; Crohn's disease and ulcerative colitis; sickle cell anemia; systemic lupus erythematosus; hemolytic uremic syndrome; epilepsy; smoking over 35 years of age; prolonged immobilization, major surgical interventions; fibrocystic mastopathy; uterine fibroids; diabetes mellitus; congenital hyperbilirubinemia (Gilbert, Dubin-Johnson and Rotor syndromes); chloasma (women prone to pigmentation are advised to avoid exposure to the sun or ultraviolet radiation while taking COCs).
Side effects
There are reports of the following side effects (however, their connection with the use of the drug has not been confirmed or refuted): soreness and swelling of the mammary glands and the appearance of secretions; headache, migraine; change in libido; depressive state; intolerance to contact lenses; nausea; vomiting; changes in vaginal secretions; various skin manifestations; fluid retention in the body; change in body weight; hypersensitivity reactions.
Special instructions
The daily dose of lactose contained in the tablet is so low (80 mg) that even women who are sensitive to lactose will not experience any disturbances.
reservation
If any of the conditions/risk factors listed in the section on Undesirable Effects are present, the benefits and risks of COC use should be considered individually by the doctor for each woman and discussed with the patient before she decides to take this drug. In the event of exacerbation, worsening or first appearance of any of these conditions, the woman should consult a doctor. The doctor should decide whether COC use should be continued or discontinued.
Medical examination / consultation
Before starting or resuming oral combined contraceptives, a woman should undergo a thorough medical examination, including a complete history and instrumental examinations, paying special attention to possible contraindications. Such an examination should be repeated at least once a year during the entire period of taking combined contraceptives. Periodic medical assessment is important for contraindications (for example, cerebrovascular accident) or risk factors (for example, the presence of venous or arterial thrombosis in relatives) that may arise for the first time during the period of taking contraceptives. The frequency and nature of such examinations are set individually for each woman, but in general they should include blood pressure measurement, examination of the mammary glands, abdominal cavity and pelvic organs, cytological examination of the cervical epithelium and appropriate laboratory tests.
It is necessary to explain to women that oral contraceptives do not protect against HIV/AIDS and other sexually transmitted diseases.
decreased efficiency
The effectiveness of COCs may be reduced if tablets are missed (see Method of administration), gastrointestinal disorders or when certain medicines are taken at the same time (see Interactions with other medicines).
Worsening menstrual cycle control
If irregular bleeding persists or occurs after previously regular cycles, possible non-hormonal causes should be considered and necessary diagnostic tests should be performed to exclude pregnancy or tumor; curettage may be performed.
In some women, withdrawal bleeding may not occur during the tablet-free period. If the COC has been used according to the instructions, the likelihood of pregnancy is low. However, if these instructions have been violated in the period before the first absence of bleeding in the tablet-free period or if bleeding is absent twice in a row, pregnancy should be excluded before continuing COC use.
Use of the drug during pregnancy and / or breastfeeding. Pregnancy is a contraindication for the use of Marvelon. If a woman becomes pregnant while taking Marvelon, further administration should be stopped immediately. Studies have not revealed either an increased risk of pathology in children born to mothers who took COCs before pregnancy, or a teratogenic effect of COCs that were inadvertently taken at the beginning of pregnancy.
Estrogens affect lactation, as they can reduce the amount and change the composition of breast milk, but there are no signs of a negative effect on the health of breast-fed infants. However, it is not recommended to use COCs during breastfeeding, and if necessary, breastfeeding should be completely discontinued.
Impact on the ability to drive vehicles. The ability to concentrate is not affected.
Interactions
Interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or a weakening of the contraceptive effect of the drug. Interactions may occur with drugs that induce microsomal enzymes, which may lead to increased metabolism of sex hormones. Such drugs include phenytoin, barbiturates, primidone, carbamazepine, rifampicin and possibly also oxcarbazepine, topiramate, felbamate, ritonavir, griseofulvin and drugs containing St. John's wort. The effectiveness of the drug may also be reduced by concomitant administration of certain antibiotics, such as penicillins and tetracyclines. These drugs reduce the enterohepatic circulation of estrogens, which leads to a decrease in the concentration of ethinylestradiol.
Women taking any of these drugs should temporarily use a barrier method of contraception in addition to the COC or choose another method of protection against unwanted pregnancy. Women taking antibiotics (except rifampicin and griseofulvin) should use a barrier method during the period of taking the corresponding drug and for 7 days after its withdrawal. When taking enzyme-inducing drugs, a barrier method should be used in addition to the COC during the entire period of treatment and for 28 days after stopping treatment. If the administration of the drug is to be continued, and the tablets in the COC package have already ended, the next package should be started immediately, without the usual break.
COCs may affect the metabolism of other drugs. Accordingly, the concentration of such drugs (e.g. cyclosporine) in blood plasma and tissues may change.
Note: To determine a possible interaction, the prescribing information for the concomitant medication should be consulted.
Laboratory tests. Contraceptive steroids may affect the results of certain laboratory tests, including biochemical indicators of liver, kidney, thyroid, adrenal function, serum protein (carrier) levels, such as corticosteroid-binding globulin and/or lipid/lipoprotein fractions, indicators of carbohydrate metabolism, coagulation, and fibrinolysis. Changes usually remain within normal limits.
Overdose
No significant adverse effects have been reported in overdose. The following symptoms may occur: nausea, vomiting, and in girls - slight vaginal bleeding. There is no antidote. If necessary, symptomatic therapy is indicated.
Storage conditions
In a place protected from light and moisture at a temperature of 2-30 °C.
