The contraceptive effect of is carried out by means of complementary mechanisms, the most important of which are inhibition of ovulation and changes in the properties of cervical secretions, causing it becomes impermeable to sperm.
In women taking combined oral contraceptives, menstrual cycle becomes more regular, less what is testosterone propionate often observed painful menstruation, it decreases the amount of bleeding, thereby reducing the risk of iron deficiency anemia. Furthermore, there is evidence that reduces the risk of endometrial cancer and ovarian cancer.
While taking is reduced increased activity of the sebaceous glands, which plays an important role in the occurrence of acne and seborrhea. After 3-4 months of therapy it usually leads to the disappearance of existing scars. Excessive oiliness of hair and skin disappears earlier. It also reduces hair loss, often accompanied by seborrhea. Therapy of in women of reproductive age reduces the clinical manifestations of mild forms of hirsutism (particularly increased hair growth on the face); however, the effect of treatment can be expected only after several months of use. Along with the above-described anti-androgenic effect, cyproterone acetate and has a pronounced progestational action.
Absorption. When administered cyproterone acetate is completely absorbed over a wide dose range. After ingestion of 35 dragees Diana maximum concentration (Cmax) in the serum cyproterone acetate equal to 15 ng / ml, is reached after 1.6 hours. The absolute bioavailability of cyproterone acetate is almost complete (88% of the dose). Distribution.
Cyproterone acetate only binds with serum albumin. The free form is only about 3.5-4% of the total serum concentration. GTN ethinylestradiol induced increase does not affect the binding of serum proteins cyproterone acetate. Average apparent volume of distribution is 986 ± 437 l
Metabolism. Cyproterone acetate is metabolized by two pathways, including hydroxylation and conjugation. Major metabolite in human plasma -15R-hydroxy derivative.
Withdrawal. Some of the dose is excreted unchanged in the bile. Most of the dose excreted in urine as metabolites or bile in the ratio 1: 2. The metabolites are eliminated from plasma with a half-life of 1.8 days.
The equilibrium concentration. As protein binding is not specific changes globulin levels binding sex steroids (GSM) have no effect on the pharmacokinetics of cyproterone acetate. During treatment cyclic maximum equilibrium concentration of cyproterone acetate in the serum obtained in the second half cycle.
Absorption. After oral administration, ethinylestradiol is rapidly and completely absorbed. The maximum concentration (Cmax) in the serum of approximately 71 pg / ml, achieved after 1.6 hours. During the suction and the first passage through the liver is metabolized ethinylestradiol, whereby its oral bioavailability averages about 45%.
Distribution. Ethinyl estradiol is almost full (about 98%), while non-specifically binds to albumin. Ethinyl estradiol induces the synthesis of SHBG. The apparent volume of distribution of ethinylestradiol is 2,8 8,6 l / kg.
Metabolism. Ethinylestradiol undergoes conjugation presistemna as mucosa of the small intestine and in the liver. The main pathway – aromatic hydroxylation. The rate of clearance from the blood plasma of 2,3-7 ml / min / kg.
. Withdrawal A decrease in serum concentrations of ethinyl estradiol is biphasic; The first phase is characterized by a half-life of about 1 hour, The second one is 10-20 hours. In an unmodified form of the organism is not displayed. Ethinylestradiol metabolites are excreted in the urine and bile in a ratio of 4: 6 with a half-life of about 24 hours.
The equilibrium concentration. The equilibrium concentration is reached during the second half of the treatment cycle
Contraception in women with symptoms of androgenization.
The treatment of androgen-dependent diseases in women, such as acne, especially common forms and shapes, accompanied by seborrhea, inflammation or nodule formation (papulopustular acne, nodulocystic acne); androgenetic alopecia and mild forms of hirsutism.
should not be applied if any of the conditions listed below. If any of these conditions develop for the first time in patients receiving the drug should be immediately repealed.
- Thrombosis (venous and arterial) and thromboembolism present or in history (including deep vein thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular accident).
- Conditions prior thrombosis (including transient ischemic attack, angina pectoris) now or in history.
- Migraine with focal neurological symptoms history
- Diabetes mellitus with vascular complications.
- Multiple or severe venous or arterial thrombosis risk factors, including valvular lesions, cardiac arrhythmia, vascular diseases of the brain or coronary arteries; uncontrolled hypertension.
- Pancreatitis with severe hypertriglyceridemia now or in history.
- Severe liver disease (as long as liver function tests have not come back to normal).
- Liver tumors (benign or malignant) now or in history.
- Identified hormone malignancies (including genital or mammary glands) or are suspected.
- Vaginal bleeding of unknown origin.
- Pregnancy or suspected it.
- The period of lactation.
- Hypersensitivity to any component of the drug
If any of the conditions / risk factors mentioned below are currently available, you should carefully weigh the potential risks and expected benefits of the use of combined oral contraceptives in each individual case:
- Risk factors for thrombosis and thromboembolism: smoking; thrombosis, myocardial infarction or cerebrovascular accident at a young age in any of the next of kin; obesity; dislipoproteinemia (eg, hypertension, migraine, valvular heart disease, cardiac arrhythmias, prolonged immobilization, major surgery, major trauma
- Other diseases in which may occur peripheral circulatory disorders: diabetes; systemic lupus erythematosus; hemolytic uremic syndrome; Crohn’s disease and ulcerative colitis; sickle cell anemia; and phlebitis of superficial veins
- liver disease
- Diseases caused or aggravated first time during pregnancy, or on the background of the previous use of sex hormones (eg, jaundice, cholestasis, gallbladder disease, otosclerosis with deterioration of hearing
Pregnancy and lactation
is not appointed during pregnancy and lactation. If pregnancy is detected during treatment , the drug should be immediately abolished. Cyproterone acetate is excreted in milk, therefore the use of is contraindicated during lactation
Dosing and Administration
Drops should be taken orally in the order indicated on the package, every day at about the same time, with a little water. Take one tablet a day continuously for 21 days. Receiving the next pack is started after a 7-day break in taking pills, during which usually occurs withdrawal bleeding. Bleeding usually begins 2-3 days after the last pellet and can not end before receiving a new package.
The duration of the androgenization depends on the severity of symptoms, as well as their response to treatment. As a general rule, treatment should continue for several months. When acne and seborrhea response usually occurs earlier than hirsutism or alopecia.
After relief of symptoms is recommended to take has, at least for 3-4 cycles. If after a few weeks or months after discontinuation of tablet-taking relapse occurs, treatment with can be resumed. If after stopping treatment relapse signs androgenization should consider the possibility of an earlier resumption of reception .
How to start taking
- Without taking any hormonal contraceptive use in the preceding month.
The reception begins on the first day of the menstrual cycle (ie the first day of menstrual bleeding). Shall start receiving 2-5 of the menstrual cycle, but in this case it is recommended to additionally use a barrier method of contraception during the first 7 days of tablet-taking from the first package.
- When switching from other combined oral contraceptives.
Preferably start taking on the day after taking the last active pills from the previous package, but in any case not later than the day after the usual 7-day break (for products containing 21 pills).
When switching from contraceptives containing only progestin ( “mini-pill”, an injectable form, implant) or releasing progestogen IUD.
a woman can go to the “mini-pill” for in any day (without a break), with the implant or intrauterine device with progestin – the date of its removal from the injection mold – the day when the next injection should have to be made. In all cases, you must use an additional barrier method of contraception during the first 7 days of tablet-taking.
- After an abortion in the first trimester of pregnancy.
A woman may start taking the drug immediately. Subject to this condition the woman does not need additional contraceptive protection.
- After delivery or abortion in the second trimester of pregnancy. It is recommended to start taking the drug on day 21-28 after delivery or abortion in the second trimester of pregnancy. If the reception is started later, you must use an additional barrier method of contraception during the first 7 days of tablet-taking. However, if a woman has been sexually active, before you start taking pregnancy must be excluded or must wait for the first menstrual period.
Admission missed pills
If the delay in receiving the drug was less than 12 hours, contraceptive protection is not reduced. The woman should take pills as soon as possible, should be taken at the usual time.
If the delay in taking pills made more than 12 hours, contraceptive protection may be reduced. It is possible to be guided by the following two basic rules:
The drug should never be interrupted for more than 7 days.
7 days continuous administration of pills required to achieve adequate suppression of the hypothalamic-pituitary-ovarian regulation.
Accordingly, these tips may be given if the delay in receiving a dragee was 12 hours (the interval since last receiving pellets over 36 hours):
• The first week of taking the drug
The woman should take the last missed pills as soon as possible, as soon as you remember (even if this means taking two pills at once). Next take the pills at the usual time. Additionally, it should be used a barrier method of contraception (such as a condom) for the next 7 days. If intercourse took place during the week before skipping pills, you need to take into account the chance of pregnancy. The more pills missed and the closer they are to a break in the reception of active substances, the greater the likelihood of pregnancy.
• The second week of taking the drug
The woman should take the last missed pills as soon as possible, as soon as you remember (even if this means taking two pills at once). Next take the pills at the usual time.
Provided that the woman has taken pills correctly in the 7 days preceding the first missed pills, there is no need to use additional contraceptive measures. Otherwise, as well as skipping of two or more must be added dragees barrier methods (such as condoms) for 7 days.
• The third week of taking the drug
The risk of reduced what is testosterone propionate reliability is imminent because of the forthcoming break in taking pills.
A woman should strictly adhere to one of the two following options. While in the 7 days preceding the first missed pills, all the pills are taken correctly, there is no need to use additional contraceptive methods.
- The woman should take the last missed pills as soon as possible, as soon as you remember (even if this means taking two pills at once). Next take the pills at the usual time until the end of the current package of pills. The next pack should be started immediately. Withdrawal bleeding is unlikely until the end of the second pack, but may experience spotting and breakthrough bleeding during the tablet-taking.
- A woman can also interrupt the reception of pills from the current package. Then she should take a break for 7 days, including the day of skipping pills, and then start receiving new packaging.
If a woman misses pills, and then during a break in taking pills she had no withdrawal bleeding, pregnancy must be excluded.
Recommendations in case of vomiting and diarrhea
If a woman has had vomiting or diarrhea within 4 hours after taking the active pills, absorption may not be complete and should be additional contraceptive measures are taken. In these cases, you should be guided by the recommendations by skipping pills.
Changing the date of the beginning of the menstrual cycle
In order to delay the onset of menstruation, the woman should continue taking pills from a new pack of immediately after taking all the pills from the previous one, without a break in the reception.Drops of this new packaging may be taken for as long as the woman wants (as long as the packaging is not finished). Against the background of the drug from the second package, women may experience spotting or breakthrough uterine bleeding. Reactivate reception should be from a new package after the usual 7-day break.
In order to move the first day of menstruation to another day of the week, the woman should be advised to shorten the next break in taking pills for as many days, as much as she wants. The shorter the interval, the higher the risk that she will not have withdrawal bleeding, and will continue to spotting and breakthrough bleeding while taking second pack (just as when she wanted to delay the onset of menstruation.
When administered combined oral contraceptives may experience irregular bleeding (spotting or breakthrough bleeding), especially during the first months of use. While taking combined oral contraceptives in women were observed and other undesirable effects.
|Body system||Often (≥1 / 100)||Uncommon (≥1 / 1000 and ≤1 / 100)||Rare (≤1 / 1000)|
|organ of vision||intolerance to contact lenses|
|Digestive tract||nausea, abdominal pain||vomiting, diarrhea|
|The immune system||hypersensitivity reactions|
|Common symptoms||weight gain||Weight loss|
|psychiatric disorders||depressed mood, mood swings||decreased libido||increase libido|
|Reproductive system and mammary glands||breast pain, breast engorgement||hypertrophy breast||vaginal discharge, discharge from the breast|
|Skin and subcutaneous tissue||rash, urticaria||erythema nodosum, multiforme|
As when taking other combined oral contraceptives in the rare cases of thrombosis and thromboembolism (see. Also “Special Instructions”).
No serious violations were reported in overdose. Symptoms that may occur with overdose include nausea, vomiting, spotting or metrorrhagia. No specific antidote, symptomatic treatment should be conducted.
Interactions with other drugs
Interactions of oral contraceptives with other drugs may lead to breakthrough bleeding and / or reduce the contraceptive reliability. The literature reports the following types of interaction.
Effect on hepatic metabolism: use of drugs that induce hepatic microsomal enzymes which may lead to increased clearance of sex hormones. These medicines include: phenytoin, barbiturates, primidone, carbamazepine, rifampicin; also there are suggestions with regard to oxcarbazepine, topiramate, felbamate, ritonavir and griseofulvin and products containing St. John’s wort.
Effect on the enterohepatic circulation: According to separate studies, some antibiotics (such as penicillins and tetracyclines) may reduce the enterohepatic circulation of estrogen, thereby decreasing the concentration of ethinyl estradiol.
During reception drugs affecting microsomal enzymes and for 28 days after their removal should additionally use a barrier method of contraception.
During reception of antibiotics (such as ampicillin and tetracycline) and for 7 days after their removal should additionally use a barrier method of contraception. If the period of use of barrier methods of protection ends later than Bean in a package, you need to move on to the next pack of without the usual break in taking pills. Combination oral contraceptives may affect the metabolism of other drugs (including Cyclosporine), which leads to a change in their concentration in the plasma and tissues.
If any of the conditions / risk factors mentioned below are currently available, you should carefully weigh the potential risks and expected benefits of the treatment of in each individual case and discussed with the woman before she decides to start taking drug. In the case of aggravation, or amplification of the first manifestations of any of these conditions or risk factors, the woman should consult with your doctor, who can decide whether to cancel the drug.
Diseases of the cardiovascular system
are available to increase the data rate of venous and arterial thrombosis and thromboembolism (such as deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) when taking combined oral contraceptives.
The risk of developing venous thromboembolism (VTE) is greatest in the first year of receiving such drugs. The approximate incidence of VTE in women taking low-dose oral contraceptives (<0.05 mg ethinylestradiol) is up to 4 per 10 000 person / years compared to 0.5-3 per 10 000 person / years among women who do not use combined oral contraceptives. The incidence of VTE in the background of pregnancy is 6 per 10 000 person / years.
The risk of thrombosis (venous and / or arterial) and thromboembolism is increased:
- with age
- smokers (with the number of cigarettes or increasing age the risk further increases, especially in women over 35 years old);in the presence of:
- family history (ie venous or arterial thromboembolism ever in close relatives or parents at a relatively young age); in the case of hereditary predisposition, the woman should be assessed and the appropriate specialist to resolve the question of the possibility of using combined oral contraceptives;
- obesity (body mass index over 30 kg / m);
- diseases of the heart valves;
- atrial fibrillation;
- prolonged immobilization, what is testosterone propionate major surgery, any surgery to the legs, or major trauma. In these situations, it is desirable to discontinue the use of combined oral contraceptive (in case the intended operation of at least four weeks prior to it) and not to resume reception within two weeks after the immobilization.
The question of the possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism remains controversial. It is necessary to take into account the increased risk of thromboembolism during the postpartum period. Peripheral circulatory disorders also may occur in diabetes mellitus, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis) and sickle cell anemia. Increased frequency and severity of migraine during use of combined oral contraceptives (which may be preceded by a cerebrovascular accident) may be a reason for immediate discontinuation of these drugs. • tumors has been reported some increase in the risk of cervical cancer in long-term use of combined oral contraceptives.Communication with the reception of combined oral contraceptives has not been proved. Contradictions persist as to the extent to which these findings are associated with screening for cervical abnormalities or with features of sexual behavior (a rare use of barrier methods of contraception). The most important risk factor for cervical cancer is persistent papilloma virus infection.
It was also found that there is a slightly increased relative risk of developing breast cancer diagnosed in women who used combined oral contraceptives. The increased risk disappears gradually within 10 years after discontinuation of these drugs. His connection with the intake of combined oral contraceptives has not been proved. The observed increase in risk may also be due to an earlier diagnosis of breast cancer in women who use combined oral contraceptives. In women, ever use a combined oral contraceptives, revealed earlier stages of breast cancer than women who never let them apply. In rare cases, against the background of the use of combined oral contraceptives was observed the development of liver tumors, which in some cases led to life-threatening intra-abdominal haemorrhage. In case of severe pain in the abdomen, liver enlargement or signs of intra-abdominal bleeding it should be considered in the differential diagnosis.
Women with hypertriglyceridemia (in the presence of this condition in the family history) may increase the risk of developing pancreatitis while taking combined oral contraceptives.
Although a slight increase in blood pressure have been reported in many women taking COCs, clinically relevant increases were rare. However, if while taking combined oral contraceptives develops persistent, clinically significant increase in blood pressure, should be discontinued these drugs and begin treatment of hypertension. Receiving COCs can be continued, if using antihypertensive therapy achieved normal blood pressure values.
The following conditions have been reported to develop or worsen both during pregnancy and when taking combined oral contraceptives, but their relationship with the intake of combined oral contraceptives has not been proven: jaundice and / or pruritus related to cholestasis; the formation of gallstones; porphyria; systemic lupus erythematosus; hemolytic uremic syndrome; chorea; herpes gestationis; hearing loss associated with otosclerosis. cases of Crohn’s disease are also described and ulcerative colitis background on the use of combined oral contraceptives.
Sometimes it can develop chloasma, especially in women with a history of chloasma during pregnancy. Women with a tendency to chloasma while taking combined oral contraceptives should avoid prolonged exposure to sunlight and ultraviolet radiation. Acute or chronic disturbances of liver function may require the cancellation of combined oral contraceptives, as long as liver function tests have not returned to normal. Relapse cholestatic jaundice that developed first during pregnancy or previous use of sex hormones, requires discontinuation of COCs.
Although COCs may have an effect on insulin resistance and glucose tolerance, there is no need to change the therapeutic regimen in diabetics using low-dose COCs (<0.05 mg ethinylestradiol). However, women with diabetes should be carefully monitored during the reception of combined oral contraceptives.
If a woman suffering from hirsutism, symptoms have recently emerged or are expressed to a large extent, the differential diagnosis in order to identify possible causes of the disease (androgen tumor, adrenal enzyme deficiency) should be conducted.
using combined oral contraceptives can affect the results of certain lab tests, including liver function, kidney, thyroid, adrenal, levels of transport proteins in the plasma, carbohydrate metabolism, coagulation and fibrinolysis parameters. Changes do not usually go beyond the normal range.
The effect on the menstrual cycle
While taking combined oral contraceptives may experience irregular bleeding (spotting or breakthrough bleeding), especially during the first months of use. Therefore, the evaluation of any irregular bleeding should be done only after a period of adaptation of approximately three cycles. If irregular bleeding recur or develop after previous regular cycles, you should conduct a thorough examination to exclude malignancy or pregnancy.
In some women, during a break in taking pills may not develop withdrawal bleeding. If combined oral contraceptives are taken according to directions, it is unlikely that the woman is pregnant. Nevertheless, if before that combined oral contraceptives are taken irregularly or if there are no two consecutive withdrawal bleeding, to continue receiving the drug should be excluded pregnancy.
recommended to undergo a thorough general medical and gynecological examination before the start of the drug women (including the study of mammary glands and cytological examination of cervical secretions), exclude pregnancy. In addition, to exclude blood coagulation disorders.
In the case of long-term use of the drug is necessary every 6 months to conduct follow-up examinations.
It should warn the woman that drugs such as does not protect against HIV infection (AIDS) and other sexually transmitted diseases through!