The instruction for medical use
of BELARA® medicine
the Trade name
the International unlicensed name
Is not present
the Dosage form
of the Tablet, film coated, 2 mg / 0.03 mg
One tablet contains
active agents: chlormadinona acetate of 2 mg, ethinylestradiol of 0.03 mg,
excipients: magnesium stearate, povidone-K30, starch corn, lactoses monohydrate,
film cover: ferrous oxide red (E 172), propylene glycol, macrogoal 6000, talc, titan dioxide (E 171), lactoses monohydrate, gipromelloza.
of the Tablet of round shape, with a biconvex surface, film coated light pink color. Kernel of white or almost white color
Sex hormones and modulators of a reproductive system. Hormonal contraceptives for system use. Progestogens and estrogen (the fixed combinations)
the ATH Code: G03AA
Chlormadinon’s Pharmacokinetics properties acetate (HMA)
After intake of HMA is quickly and almost completely soaked up. System bioavailability of HMA high as it is not exposed to primary metabolism in a liver. The maximum concentration in blood plasma is reached in 1-2 hours.
More than 95% of HMA contacts proteins of blood plasma, generally albumine. HMA does not contact the globulin connecting sex hormones or with the globulin connecting cortisol. HMA collects mainly in fatty tissue.
Various processes of restoration, oxidation and linking with glucuronides and sulfates lead metabolism to formation of a set of metabolites. The main metabolites in blood plasma are 3α- and 3β-гидрокси-ХМА with elimination half-life, significantly not different from nemetabolizirovanny HMA. 3-hydroxies-metabolites have the anti-androgenic activity similar to activity of the HMA. In urine the metabolites contain in the basic in the form of conjugates. After zymolysis becomes the main metabolite 2α-гидрокси-ХМА, 3-hydroxies-metabolites and dihydroxymetabolites are also formed.
Average elimination half-life of HMA makes about 34 hours of blood plasma (after a single dose) and about 36-39 hours (after repeated use). After oral administration HMA and its metabolites are removed in approximately equal quantities, both through kidneys, and through intestines.
of EE is quickly and almost completely soaked up after intake, reaching the maximum concentration in blood plasma in 1.5 hours. Owing to presistemny binding and metabolism in a liver the absolute bioavailability is only about 40% and is subject to strong individual variability (20-65%).
The data on concentration of EE which are Available in literature in blood plasma strongly vary distribution. About 98% of ethinylestradiol contact proteins of blood plasma, is almost exclusive with albumine.
As well as natural estrogen, EE biotransformirutsya through hydroxylation of an aromatic ring (a mediator is the system of R-450 cytochrome). The main metabolite is 2-hydroksi-EE which is transformed to other metabolites and conjugates. Ethinylestradiol is exposed to presistemny binding both in a mucous membrane of a small intestine, and in a liver. In urine find, generally glucuronides, and in bile and blood plasma – sulfates.
Average elimination half-life of EE makes about 12-14 hours of blood plasma. EE is removed by kidneys and through intestines in the ratio 2:3. The EE sulfate removed with bile after hydrolysis by colibacilli is exposed to enterohepatic recirculation.
Continuous use of the drug Belara® within 21 days suppresses secretion of follicle-stimulating hormone (FSG) and luteinizing hormone (LH) a hypophysis and, as a result, suppresses an ovulation. Proliferation of endometrium and its secretory transformation is observed. Also the consistence of cervical slime changes. It complicates passing of spermatozoa via the cervical channel and leads to disturbance of their mobility.
The minimum dose of a chlormadinon of acetate providing full suppression of an ovulation makes 1.7 mg. The dose necessary for endometrium transformation makes 25 mg on a cycle.
Chlormadinona acetate is progestogen with anti-androgenic properties. The mechanism of its action is based on ability to substitute androgens on specific receptors.
– hormonal contraception
the Route of administration and doses
begin Reception of tablets from the first day of a menstrual cycle on 1 tablet every day at the same time (preferably in the evening) within 21 days in a row, then it is necessary to take a 7-day break in reception of tablets, in two-four days after reception of the last tablet, there will be bleeding of cancellation, similar to menstrual bleeding. After the termination of a seven-day break it is necessary to start administration of drug of Belara® from the following pack irrespective of, bleeding stopped or not.
The tablet marked corresponding day of the week should be taken from the blister packing and to swallow entirely, if necessary having washed down with a small amount of water. A pill should be taken every day, following in the direction specified by an arrow.
The beginning of reception of tablets
If hormonal contraceptives were not applied earlier (during the last menstrual cycle)
the First tablet, it is necessary to accept in the first day of a natural cycle of the woman, i.e. in the first day of the following menstrual bleeding. If the first pill is taken in the first day of periods, contraceptive effect of drug begins from the first day of reception and continues during a seven-day break in reception of tablets.
The first pill can be also taken for 2-5 day of periods irrespective of, bleeding stopped or not. In this case during the first seven days of reception it is necessary to use additional barrier methods of contraception.
If the periods began more than five days ago, the woman should recommend to wait for the beginning of the following periods to start administration of drug of Belara®.
Transition from other hormonal contraceptive to administration of drug of Belara®
the Woman should begin administration of drug of Belara® next day after a seven-day break in reception of tablets or reception of tablets placebos from packing of earlier used combined oral contraceptive.
Transition from the drugs containing only progestogen (mini-drank)
the First tablet of the drug Belara®, it is necessary to accept next day after reception of the last tablet containing only progestogen. During the first seven days it is necessary to use additional barrier methods of contraception.
Transition from hormonal contraceptive injections or a contraceptive implant
Administration of drug of Belara® can be begun in day of removal of an implant or in day of initially planned injection. During the first seven days it is necessary to use additional barrier methods of contraception.
After spontaneous or medical abortion in the first trimester of pregnancy
the Administration of drug of Belara® can be begun at once after spontaneous or medical abortion in the first trimester of pregnancy. In this case there is no need for use of additional measures of contraception.
After the delivery, spontaneous or medical abortion in the second trimester of pregnancy
After the birth of the child, the women who are not nursing can begin administration of drug for 21-28 day after the delivery. In this case there is no need for use of additional barrier methods of contraception.
If administration of drug was begun more than in 28 days after the delivery, it is necessary to use additional barrier methods of contraception during the first seven days.
If the woman already had a sexual intercourse, it is necessary to exclude pregnancy existence, or to wait for the beginning of the following menstrual cycle before beginning administration of drug.
After the termination of administration of drug of Belara®
After the termination of administration of drug of Belara® the current cycle can be extended approximately for one week.
Irregular reception of tablets
If the patient forgot to take a pill, but accepted it within the next 12 hours, additional measures of contraception are not required. The patient has to continue administration of drug in the usual mode.
If the patient forgot to take a pill, but accepted it after 12 hours, contraceptive protection can be reduced. In case of the admission of reception of a tablet it is necessary to work, being guided by the following two basic rules:
1. never it is impossible to interrupt reception of tablets more than for seven days
2. the 7-day break in reception of tablets is necessary for achievement of sufficient suppression of an axis a hypothalamus – a hypophysis – an ovary.
The last (forgotten) tablet, it is necessary to accept immediately even if it means that it is necessary to take 2 pill at the same time. Other pill should be taken as usual. During the next seven days it is necessary to use in addition barrier methods of contraception, for example, condoms. If reception of tablets was missed within 1 week of a cycle, and within seven days to the passed tablets there was a sexual intercourse (including a seven-day break in reception of tablets), it is necessary to consider pregnancy approach probability. What the bigger quantity of tablets was passed by, and the they were closer on terms to a usual break in reception of tablets, the pregnancy approach probability is higher.
If in the used pack there were less than seven tablets, at once after the end of reception of tablets from the used pack it is necessary to begin to take a pill from new packing of the drug Belara®, i.e. there should not be a break between two packs. Possibly, common bleeding of cancellation will not arise, tablets from the second packing will not end, however, during reception of tablets from new packing perhaps appearance of the breakthrough or smearing bleeding yet. If bleeding of cancellation does not arise after the end of reception of tablets from the second packing, it is necessary to make the test for pregnancy.
Recommendations in case of vomiting or diarrhea
If vomiting or severe diarrhea arose within 4 hours after reception of a tablet, absorption of drug can be incomplete, therefore, reliability of contraception cannot be guaranteed. In this case it is necessary to work according to the recommendations provided in the section Irregular Reception of Tablets. It is necessary to continue administration of drug of Belara®.
How to delay bleeding of cancellation
to delay bleeding, the woman has to continue reception of tablets from the following packing of the drug Belara®, without taking a break. It is possible to continue reception of tablets at will until tablets from the second packing end. During reception of tablets from the second packing the emergence of insignificant bloody discharges or breakthrough bleeding is possible. After a usual 7-day break in reception of tablets it is necessary to resume regular administration of drug of Belara®. To shift the beginning of bleeding the next day of week, other than day of the beginning of bleeding on the existing scheme, the woman can recommend to reduce the following seven-day break by the desirable number of days. The shorter having rummaged in reception of tablets, the risk of absence of bleeding of cancellation and development of breakthrough bleeding or insignificant bloody discharges is higher during reception of tablets from the following packing (as well as when delaying bleeding).
Very often ((& gt, 1/10)
– breakthrough bleedings, insignificant bloody discharges, a dysmenorrhea, an amenorrhea, discharges from a vagina
– a headache
– discomfort in mammary glands
Often (& gt, 1/100 to & lt, 1/10)
– dizziness, migraine (and/or strengthening of migraine)
– suppressed mood, nervousness, irritability, fatigue
– heavy feeling
– an acne
– pain in the bottom of a stomach
– hypostases, increase in body weight
– increase in arterial blood pressure
– a disorder of vision
Infrequently (& gt, 1/1,000 to & lt, 1/100)
– hypersensitivity to drug, including skin allergic reactions
– an abdominal pain, an abdominal distension, diarrhea
– disturbances of pigmentation, a hloazm, an alopecia, xeroderma
– a dorsodynia, muscular disturbances
– a galactorrhoea, a fibroadenoma of a mammary gland, vagina candidiasis
– decrease in a libido, a hyperhidrosis
– changes of maintenance of lipids in blood, including a gipertriglitseridemiya
Seldom (& gt, 1/10,000 to & lt, 1/1,000)
– conjunctivitis, intolerance of contact lenses
– a sudden hearing loss, sonitus
– arterial hypertension, arterial hypotension, a syncope, a varicosity, a vein thrombosis
– urtikarny rash, eczema, an itching, exacerbation of psoriasis, a hypertrichosis
– increase in mammary glands, a vulvovaginitis, a menorrhagia, a premenstrual syndrome
– strengthening of appetite
is Very rare (& lt, 1/1 0000)
– a nodular erythema
At use of the combined oral contraceptives (COOK) including 0.03 mg of ethinylestradiol and 2 mg of a chlormadinon of acetate, were also reported about the following side effects:
· It is known that use of the combined oral contraceptives is connected with the increased risk of a venous and arterial thrombembolia (for example, a vein thrombosis, an embolism of a pulmonary artery, a stroke, a myocardial infarction).
· According to some researches prolonged use the COOK increases risk of developing diseases of biliary tract.
· In rare instances after reception of oral contraceptives cases of developing of benign tumors of a liver were registered, malignant tumors were registered even less often, in some cases these tumors were the reason of life-threatening intra belly bleeding.
· Exacerbation of chronic inflammatory bowel diseases (Crohn’s disease, ulcer colitis).
– being available earlier or existing thromboses of vein or arteries (for example, a deep vein thrombosis, an embolism of a pulmonary artery, a myocardial infarction or a stroke)
– a prodromal stage or the first symptoms of thrombosis, thrombophlebitis or embolism symptoms (for example, the tranzitorny ischemic attack, stenocardia)
– the planned surgery (at least in four weeks prior to operation) and also the immobilization period (for example, after injuries)
– the diabetes which is followed by vascular complications
– the diabetes which is not giving in to control
– uncontrollable arterial hypertension or substantial increase of arterial blood pressure (the values which are constantly exceeding 140/90 mm Hg.)
– the hereditary or acquired predisposition to thrombosis of vein or arteries, such as resistance to the activated protein With, deficiency of antithrombin III, deficit of a protein With, deficit of a protein of S, a gipergomotsisteinemiya and antibodies to phospholipids (antibodies to anti-cardiolipin, lupoid anticoagulant)
– hepatitis, jaundice, abnormal liver functions before normalization of indicators of function of a liver
– a generalized itching, a cholestasia, in particular during the previous pregnancy or therapy by estrogen
– a syndrome the Cudgel Johnson, a syndrome of the Rotor, biliation disturbance
– a liver tumor (including in the anamnesis)
– severe pain in epigastriums, increase in a liver or symptoms of intra belly bleeding
– the porphyria which arose for the first time or recuring (all three forms, in particular the acquired porphyria)
– the malignant hormonedependent tumors in the anamnesis or existing (for example, tumors of mammary glands or a uterus)
– serious violations of lipid metabolism
– the pancreatitis (including in the anamnesis) which is followed by a heavy gipertriglitseridemiya
– for the first time the arisen migraine symptoms and also more frequent and extraordinary severe headache
– migraine with focal neurologic symptomatology in the anamnesis (the migraine form which is combined with paresthesias, spasms, aphasia)
– sudden disturbances from sense bodys, for example, of a disorder of vision or hearing
– motive disturbances (in particular, paresis)
– strengthening of epileptic seizures
– a heavy depression
– the otosclerosis progressing during the previous pregnancies
– an amenorrhea of not clear etiology
– an endometrium hyperplasia
– bleedings from a vagina of not clear etiology
– hypersensitivity to active ingredients or to any other component of drug
– pregnancy and the period of a lactation
– the intolerance of a galactose, a lactose intolerance or a sprue of glucose and a galactose
Interaction of ethinylestradiol, an estrogenic component of the drug Belara® with other medicines can cause increase or decrease in concentration of ethinylestradiol in blood serum. In need of long-term treatment by these active agents it is necessary to use non-hormonal methods of contraception. Decrease in concentration of ethinylestradiol in blood serum can lead to increase of episodes of breakthrough bleedings, disturbance of a cycle and decrease in contraceptive efficiency of the drug Belara®, increase in concentration of ethinylestradiol in blood serum can lead to increase in frequency and weight of side effects.
The following medicines / active ingredients can reduce concentration of ethinylestradiol in blood serum:
– all medicines enhancing motility of digestive tract (for example, Metoclopramidum) or breaking absorption (for example, activated carbon)
– the substances inducing microsomal enzymes of a liver, such as rifampicin, rifabutin, barbiturates, anticonvulsant drugs (for example, carbamazepine, Phenytoinum or topiramat), griseofulvin, barbeksaklon, Primidonum, modafinit, some inhibitors of proteases (for example, ritonavir) and drugs of the St. John’s wort which is made a hole
– some antibiotics (for example, ampicillin, tetracycline) at some women, perhaps, thanks to decrease in enterohepatic recirculation of estrogen.
At simultaneous short-term use of these medicines / active ingredients with the drug Belara® it is necessary to use additional barrier methods of contraception, both during treatment, and during the first seven days after its termination. At intake of the active ingredients reducing concentration of ethinylestradiol in blood serum due to induction of microsomal enzymes of a liver, additional barrier methods should be applied within 28 days after the end of treatment.
If intake of the accompanying medicine it is necessary to continue after the termination of tablets in the blister packing the COOK, then it is necessary to begin reception of tablets from the following packing, without taking a usual seven-day break.
The following medicines / active agents can increase concentration of ethinylestradiol in blood serum:
– the active ingredients suppressing sulphation of ethinylestradiol in an intestines wall, for example, ascorbic acid or paracetamol
– atorvastatin (increases AUC ethinylestradiol by 20%)
– the active ingredients suppressing activity of liver microsomal enzymes such as antifungal means which are imidazole derivatives (for example, flukonazol), indinavir or troleandomitsin.
Ethinylestradiol can affect metabolism of other substances:
– to suppress activity of microsomal enzymes of a liver and, respectively, to increase concentration in blood serum of such active ingredients as diazepam (and other benzodiazepines which metabolism is carried out by means of hydroxylation), cyclosporine, theophylline and Prednisolonum
– to induce a glyukuronization in a liver and, respectively, to reduce concentration in blood serum of such substances as Clofibratum, paracetamol, morphine and lorazepam.
The need for insulin and oral hypoglycemic means as drug affects tolerance to glucose can change.
Together with the drug Belara® it is not necessary to take the medicines of plant origin containing a St. John’s wort made a hole (Hypericum perforatum).
Indicators of some laboratory researches can change against the background of reception the COOK, for example, indicators of function of a liver, thyroid gland, adrenal glands, levels of proteins of carriers in plasma (for example, the globulin, connecting sex hormones (G,CSH), lipoproteins) and also parameters of carbohydrate metabolism, coagulation and fibrinolysis. The character and extent of change of laboratory indicators depend on what hormones are used and in what doses.
instructions Smoking are increased by risk of the serious cardiovascular complications connected with reception of the combined oral contraceptives (COOK). The risk increases with age and at increase in quantity of the smoked cigarettes and is high at women 35 years are more senior. The smoking women are more senior than 35 years have to use other methods of contraception.
Use the COOK is connected with the increased risk of various serious diseases, such as myocardial infarction, thrombembolia, stroke or new growths of a liver. Other risk factors, such as arterial hypertension, a lipidemia, obesity and diabetes significantly increase risk of complications and mortality.
In the presence of one of the following diseases / risk factors it is necessary to weigh potential risk and the expected advantage of drug Belara® use and also to discuss it with the woman before she begins reception of tablets. If these diseases or risk factors arise or progress during drug use, the patient has to consult with the attending physician. The doctor has to make the decision on whether it is necessary to continue or stop treatment.
The thrombembolia or other vascular diseases
Results of epidemiological researches show that there is an interrelation between reception of oral contraceptives and increase in risk of venous and arterial thromboembolic diseases, for example, of a myocardial infarction, cerebral hemorrhages, a deep vein thrombosis and an embolism of a pulmonary artery. These diseases develop seldom.
Use the COOK involves higher risk of a venous thrombembolia (VTE), than at abstention from their reception. Such risk of VTE is highest at women within the first year of use of the combined oral contraceptives. This risk is less than risk of VTE connected with pregnancy which is 60 cases on 100,000 pregnancies, VTE leads to death in 1-2% of cases.
It is unknown how administration of drug of Belara® affects risk of VTE in comparison with other combined oral contraceptives.
Risk of developing a venous thrombembolia at the women accepting the COOK increases in the following cases:
· with age
· with genetic predisposition (for example, a venous thrombembolia at brothers and sisters or parents at relatively young age). In the presence of suspicions on genetic predisposition, the woman it is necessary to direct to reception to the expert before making decision on a possibility of appointment the COOK
· at a long immobilization
· in obesity (body mass index more than 30 kg/sq.m)
Risk of developing an arterial thrombembolia increases in the presence of the following factors:
· the age is more senior than 35 years
· obesity (body mass index more than 30 kg/sq.m)
· arterial hypertension
· valvular heart disease
· fibrillation of auricles
· presence of genetic predisposition (for example, an arterial thrombembolia at brothers and sisters or parents at relatively young age). In the presence of suspicions on genetic predisposition the woman should be directed to reception to the expert before making decision on reception the COOK
Other diseases influencing blood circulation diabetes, a system lupus erythematosus, a gemolitiko-uraemic syndrome, chronic inflammatory bowel diseases (Crohn’s disease and ulcer colitis) and also a sickemia are.
At ratio assessment the advantage/risk of drug should be remembered that adequate treatment of the above-stated diseases can reduce risk of thrombosis.
It is also necessary to consider that the risk of tromboembolic episodes increases during a puerperal period.
There is no consensus concerning whether there is an interrelation between superficial thrombophlebitis and/or a varicosity and an etiology of a venous thrombembolia.
Possible symptoms of a vein thrombosis and arteries is the following:
· pain and/or swelled in a leg
· sudden severe pain in a breast irrespective of, it gives to the left hand or not
· a sudden attack of short wind, sudden cough for the unknown reason
· unexpectedly severe and long headache
· partial or total loss of sight, diplopia/disturbance of the speech or aphasia
· dizziness, a faint, in certain cases including focal epileptic seizures
· sudden weakness or a dizesteziya in one side of a body or a part of a body
· motive disturbances
· an acute pain in
the Patient’s stomach, accepting the COOK, have to be informed that in case of possible symptoms of thrombosis they should see a doctor. At suspicion or confirmation of thrombosis the administration of drug of Belara® should be stopped.
Increase in frequency and intensity of attacks of migraine against the background of use the COOK (that can indicate a prodromal phase of disturbance of blood supply of a brain), can be the indication to the immediate termination of administration of drug.
Some epidemiological researches demonstrate that long reception of oral contraceptives is risk factor of developing cervical cancer at the women infected with the virus of a pappiloma of the person (VPP). However, this issue is controversial as it is not clear to what degree other factors affect the received results (for example, differences in the number of sexual partners or use of barrier methods of contraception).
Meta-analysis of 54 pharmako-epidemiological researches showed that relative risk of developing breast cancer is slightly higher at the women accepting the COOK (RR = 1.24). This increased risk gradually decreases within 10 years after the reception termination the COOK. However, these researches did not confirm existence of relationship of cause and effect between a disease and administration of drug. The observed increased risk can speak the fact that at the women accepting the COOK, breast cancer is diagnosed at earlier stage, than for those who do not apply them and also biological effect the COOK or a combination of both factors.
In rare instances after reception of oral contraceptives cases of developing of benign tumors of a liver were registered, malignant tumors were registered even less often. In some cases these tumors can provoke life-threatening intra belly bleeding. In case of appearance of severe pain in a stomach which does not disappear independently a hepatomegalia or symptoms of intra belly bleeding, it is necessary to consider a likelihood of developing a tumor of a liver, administration of drug of Belara® should be stopped.
At many women accepting oral contraceptives the slight increase of arterial blood pressure is noted. Clinically significant increase in the ABP is observed seldom. The interrelation between use of oral contraceptives and clinically shown arterial hypertension is at the moment not confirmed. If against the background of administration of drug of Belara® clinically significant increase in arterial blood pressure is observed, it is necessary to stop administration of drug and to carry out treatment of arterial hypertension. As soon as indicators of arterial blood pressure are normalized after performing hypotensive therapy, administration of drug of Belara® can be continued.
At the women having herpes of pregnant women in the anamnesis against the background of reception the COOK is possible a recurrence of this disease. Women, in the anamnesis or the family anamnesis of which have instructions on a gipertriglitseridemiya, against the background of reception the COOK raises risk of developing pancreatitis. In acute or chronic abnormal liver functions the reception termination the COOK before normalization of functional indicators of a liver can be required. At a recurrence of the cholestatic jaundice for the first time diagnosed during pregnancy or intake of sex hormones it is necessary to stop reception the COOK.
Reception the COOK can affect peripheral insulin resistance or tolerance to glucose. Therefore it is necessary to watch a condition of the patients having diabetes and accepting oral contraceptives carefully.
Emergence of a hloazma, especially at the women having a hloazma of pregnant women in the anamnesis is in rare instances possible. The women predisposed to a hloazma should avoid stay in the sun and also ultraviolet radiation during reception of oral contraceptives.
Patients with rare hereditary intolerance of a galactose, a lactose intolerance of Lapp or malabsorption of glucose galactose should not take this drug.
Administration of drugs containing estrogen or estrogen/progestin can negatively affect some diseases / states. In the following cases the careful medical observation is necessary:
– multiple sclerosis
– a tetany
– bronchial asthma
– a heart or renal failure
– a chorea
– liver diseases
– a dislipoproteinemiya
– autoimmune diseases (including a system lupus erythematosus)
– arterial hypertension
– a varicosity
– disturbances of blood clotting
– a hysteromyoma
– herpes of pregnant women
– a depression
– chronic inflammatory bowel diseases (Crohn’s disease, ulcer colitis)
Before appointing to the woman oral contraceptives, it is necessary to perform medical examination and to collect the full family and personal anamnesis of the patient for the purpose of identification of contraindications and fa