Hloye

General characteristics. Structure:

Each tablet of yellow-orange color contains:
Active agents: Tsiproterona acetate of 2 mg and ethyloestradiol of 0,035 mg
Excipients:
Kernel - lactoses monohydrate, povidone, sodium carboxymethylstarch (type A), silicon dioxide colloid anhydrous, aluminum oxide colloid, magnesium stearate;
Cover - dye of Opadray Yellow IIOY-L-32901 (Opadry II Yellow OY-L-32901) (lactoses monohydrate, a gipromelloza 2910, titanium dioxide, a macrogoal 4000, ferrous oxide yellow, ferrous oxide black, ferrous oxide red, the water purified).

Each tablet of white color (placebo) contains:
Excipients:
Lactoses monohydrate, povidone, sodium carboxymethylstarch (type A), silicon dioxide colloid anhydrous, aluminum oxide colloid, magnesium stearate.

Description: Round, biconvex tablets of yellow-orange color, film coated.
Tablets (placebo) - round, biconvex tablets of white color.

Pharmacological properties:

Pharmacodynamics. The combined low-dosed monophase peroral contraceptive drug with anti-androgenic activity. The mechanism of action is caused being its part anti-androgenic drug of a steroid structure - tsiproterony by acetate and peroral estrogen - ethinylestradiol. Tsiproterona acetate has ability to contact competitively receptors of the natural androgens (testosterone, дигидроэпиандростерон, androstendion, etc.) which are formed in small amounts in an organism of women, mainly in adrenal glands, ovaries and skin.
Blocking receptors of androgens in target organs, reduces the androgenization phenomena at women (due to disturbance of the processes mediated hormone - receptor complexes at the level of the main intracellular mechanisms). Thus, there is possible a treatment of the diseases caused by the increased formation of androgens or specific sensitivity to these hormones.
Against the background of reception ХЛОЕ® the strengthened activity of sebaceous glands which plays an important role in emergence of eels and seborrheas decreases. In 3-4 months of therapy it usually leads to disappearance of the available rash. Excessive fat content of hair and skin disappears even earlier. Also the hair loss which is often accompanying seborrhea decreases. Therapy ХЛОЕ® at women of reproductive age reduces clinical manifestations of easy forms of a hirsutism; however, the effect of treatment should be expected only after several months of use.
Along with anti-androgenic properties, a tsiproterona acetate has the gestagenny activity imitating properties of hormone of a yellow body. It, as well as other medicines with gestagenny activity, oppresses secretion by a hypophysis of gonadotropic hormones and brakes an ovulation that causes its contraceptive effect.
Ethinylestradiol strengthens the central and peripheral influences of a tsiproteron of acetate on an ovulation, keeps high viscosity of cervical slime that complicates penetration of spermatozoa into a cavity of the uterus and promotes ensuring reliable contraceptive effect.
Against the background of administration of drug the cycle becomes more regular, painful periods are less often observed, will decrease intensity of bleeding therefore the risk of an iron deficiency anemia decreases.

Pharmacokinetics. Tsiproterona acetate
Absorption
 After reception ХЛОЕ® of a tsiproteron acetate is completely absorbed from the digestive tract (DT). After intake of 1 tablet HLOE® the maximum concentration in a blood plasma (Cmax) is reached in 1.6 h and makes 15 ng/ml. Bioavailability makes 88%.
Distribution
 Tsiproterona acetate almost completely contacts albumine of a blood plasma, about 3.5-4% are in a stand-at-ease. As linkng with proteins is not specific, changes of level of the globulin, connecting sexual steroids (G,CSS), do not influence pharmacokinetics of a tsiproteron of acetate. With breast milk about 0.2% of a dose of a tsiproteron of acetate are allocated.
Metabolism and removal
 The pharmacokinetics of a tsiproteron of acetate of a dvukhfazn, elimination half-life (Т½) makes 0.8 h and 2.3 days respectively for the first and second phase. The general plasma clearance makes 3.6 ml/min. The main metabolite - 15b-hydroxylic derivative Biotransformirutsya by a hydroxylation and a konjyugirovaniye. A small part - in not changed look through intestines is removed preferential in the form of metabolites by kidneys and through intestines in the ratio 1:2. Т½ for metabolites of a tsiproteron of acetate makes 1.8 days.

Ethinylestradiol
 Absorption
 After reception ХЛОЕ® ethinylestradiol is quickly and completely absorbed from a GIT. In the course of absorption and "the first passing" through a liver ethinylestradiol is exposed to intensive metabolism that causes bioavailability of equal about 45%, and its considerable individual variability. After intake of 1 dragee ХЛОЕ® Cmax makes about 80 pg/ml and is reached in 1.7 h.
Distribution
 Communication with proteins (albumine) of a blood plasma high (2% are in plasma in a free look). With breast milk about 0.02% of a dose of ethinylestradiol are allocated.
Ethinylestradiol increases hepatic synthesis GSPS and the corticosteroid-the connecting globulin (CCG) during continuous reception. Against the background of treatment ХЛОЕ® concentration of GSPS in serum increases about approximately 100th nmol/l to the 300th nmol/l, and serumal concentration of KSG increases from about 50 mkg/ml to 95 mkg/ml.
Metabolism and removal
 Pharmacokinetics of ethinylestradiol of a dvukhfazn, from Т½ 1-2 h and about 20 h respectively. Plasma clearance - about 5 ml/min. Ethinylestradiol is removed from an organism in the form of metabolites; about 40% - kidneys, 60% - through intestines.

Indications to use:

• contraception at women with the androgenization phenomena;
• androgenzavisimy diseases at women: eels (especially their expressed forms which are followed by seborrhea, the inflammatory phenomena with formation of nodes / papular and pustular eels, nodular and cystous eels/), an androgenic alopecia and easy forms of a hirsutism.

Route of administration and doses:

ХЛОЕ® accept inside on 1 tablet a day. The pill is taken, without chewing, and wash down with a small amount of liquid. Time of administration of drug does not play a role, however the subsequent reception should be made in the same chosen hour, it is more preferable after a breakfast or a dinner.
Reception ХЛОЕ® is begun in the 1st day of a cycle, using a tablet of the corresponding day of the week from calendar packaging.
Daily administration of drug is carried out, using tablets from calendar packaging consistently in the direction of the arrow applied on a foil, all pill will not be taken yet. After the end of reception of all 21 tablets of yellow-orange color from calendar packaging, it is necessary to take the remained pill of white color in the next 7 days. During the last 7 days of a medical cycle (28 days), there have to be periods (bleeding as a result of treatment cancellation). The periods usually begin in 2-3 days after the 21st day of a cycle of treatment the drug HLOE®. The following packaging needs to be begun next day after fully complete reception of tablets from the previous packaging, bleeding independently proceeds or not.
Upon transition from the combined oral contraceptives reception ХЛОЕ® should be begun next day after reception of the last tablet with active components of the previous drug, but by no means no later than the next day after a usual 7-day break in reception (for drugs, the containing 21 tablets).
Further according to the scheme described above. If the patient accepted the previous contraceptive daily within 28 days, reception ХЛОЕ® should be begun after reception of the last inactive tablet.
Upon transition from the contraceptives containing only gestagena ("mini-drank") ХЛОЕ® it is possible to begin to apply without interruption. When using injection forms of contraceptives ХЛОЕ® begin to accept from the date of when the following injection has to be made. Upon transition from an implant - in day of its removal. In all cases it is necessary to use in addition barrier method of contraception during the first 7 days of administration of drug.
After abortion in the I trimester of pregnancy the woman can begin administration of drug immediately. In this case the woman does not need additional methods of contraception.
After the delivery or abortion in the II trimester of pregnancy administration of drug should be begun for 21-28 day. If reception is begun later, it is necessary to use in addition barrier method of contraception during the first 7 days of administration of drug.
If the woman led sex life during the period between childbirth or abortion and the beginning of reception ХЛОЕ®, then at first it is necessary to exclude pregnancy or it is necessary to wait for the first periods.
The woman has to take the passed pill as soon as possible, the following tablet is accepted in usual time. At delay less than 12 h reliability of contraception does not decrease. If delay in reception of tablets made more than 12 h, reliability of contraception can be reduced.
If delay in reception of tablets made more than 12 h (an interval from the moment of reception of the last tablet more than 36 h) during the first and second week of administration of drug, then the woman has to accept last passed a tablet as soon as possible as soon as remembers (even if it means reception two a tablet at the same time). The following tablet is accepted in usual time. In addition it is necessary to use a barrier method of contraception during the next 7 days. If delay in reception of a tablet made more than 12 h (an interval from the moment of reception of the last tablet more than 36 h) during the third week of administration of drug, then the woman has to take the last passed pill as soon as possible as soon as she remembers (even if it means reception of two tablets at the same time). The following pill is taken in usual time. Besides, reception of a tablet from new packaging has to be begun as soon as the current packaging, i.e. without interruption ends. Most likely, that the woman will have no cancellation bleeding until the end of the second packaging, but at it the smearing bloody allocations or breakthrough uterine bleeding in days of reception of tablets can be observed.
If the woman had a vomiting ranging from 3 to 4 h after administration of drug, absorption of active agents can be incomplete. In this case it is necessary to be guided by recommendations at the admission of a tablet.
To delay the beginning of periods, the woman has to continue reception of tablets from new packaging of drug right after all pill from previous, without interruption in reception is taken. A pill from this new packaging can be taken as long as the woman wishes (until packaging does not end). Against the background of administration of drug from the second packaging at the woman the smearing allocations or breakthrough uterine bleedings can be noted. It is necessary to begin reception of tablets from the following packaging after completion of reception of all 28 tablets.
To transfer day began periods the next day of week, the woman should truncate the next break in reception of tablets for so many days, on how many it wants. The interval is shorter, the risk is higher that it will have no bleeding of cancellation and, further, there will be smearing bloody allocations and breakthrough bleedings during reception of the second packaging (just as in case she like to delay the beginning of periods).
At treatment of hyper androgenic states duration of reception is defined by disease severity. After disappearance of symptoms it is recommended to accept drug, at least, of 3-4 more months. In case of a recurrence in several weeks or months after end of a course it is possible to carry out repeated therapy by the drug HLOE®.

Features of use:

Before use of HLOE it is necessary to conduct all-medical examination (including mammary glands and a cytologic research of cervical slime), to exclude pregnancy, disturbances from system of a blood coagulation. At prolonged use of drug preventive control inspections it is necessary to spend each 6 months.
With risk factors it is necessary to estimate carefully potential risk and the expected advantage of therapy and to discuss it with the woman before she decides to begin administration of drug.
When weighting, strengthening or at the first manifestation of any of these states or risk factors drug withdrawal can be required.
Approximate frequency of a venous thromboembolism (VTE) at reception of oral contraceptives with a low dose of estrogen (it is less than 50 mkg of ethinylestradiol) makes to 4 on 10 Ltd companies of women a year in comparison with 0.5-3 on 10 Ltd companies of the women who are not accepting oral contraceptives. At the same time VTE frequency at reception of the combined oral contraceptives is less, than VTE frequency connected with pregnancy (6 on 10 000 pregnant women a year).
The patient has to be warned that at development of symptoms of venous or arterial thrombosis it is necessary to see a doctor immediately. These symptoms include a unilateral scelalgia and/or hypostasis; sudden severe pain in a breast with irradiation in the left hand or without irradiation; sudden asthma; sudden fit of coughing; any unusual, severe, long headache; strengthening of frequency and weight of migraine; sudden partial or total loss of sight; diplopia; inarticulate speech or aphasia; dizziness; a collapse with / or without partial attack; the weakness or very considerable anesthesia which suddenly appeared on the one hand or in one part of a body; motive disturbances; symptom complex "acute" stomach.
The interrelation between reception of the combined oral contraceptives and arterial hypertension is not established. When developing persistent arterial hypertension ХЛОЕ® it is necessary to cancel and appoint the corresponding hypotensive therapy. Reception of a contraceptive can be continued at normalization of arterial pressure.
At emergence of abnormal liver functions temporary cancellation ХЛОЕ® before normalization of laboratory indicators can be required. Recurrent cholestatic jaundice which develops for the first time in time of pregnancy or previous reception of sex hormones demands the termination of reception of the combined oral contraceptives.
Though the combined oral contraceptives exert impact on resistance of fabrics to insulin and tolerance to glucose, usually is not present need to korrigirovat a dose of hypoglycemic drugs at patients with a diabetes mellitus. Nevertheless, this category of patients has to be under careful medical observation.
Women with tendency to a hloazma during reception of the combined oral contraceptives have to avoid long stay to the sun and influences of ultraviolet radiation.
If at women with a hirsutism symptoms developed recently or considerably amplified, when carrying out the differential diagnosis it is necessary to consider other reasons, such as an androgenprodutsiruyushchy tumor, inborn dysfunction of bark of adrenal glands.
Against the background of reception ХЛОЕ® the irregular bleedings (smearing allocations or breakthrough bleedings), especially within the first months of therapy can sometimes be noted. Therefore assessment of any irregular bleedings should be carried out only after the period of adaptation making about 3 cycles.
If irregular bleedings repeat or develop after the previous regular cycles, then the non-hormonal reasons have to be considered and adequate diagnostic actions for an exception of malignant new growths or pregnancy are carried out. They can include a diagnostic scraping.
In certain cases bleeding of cancellation can not develop during a break in reception a tablet. At irregular reception of tablets or in the absence of two menstrualnopodobny bleedings in a row it is necessary to exclude pregnancy before continuation of administration of drug.
Change of results of skin allergy tests, decrease in concentration of the luteinizing hormone (LH) and follicle-stimulating hormone (FSG) is possible. Because contraceptive action is fully shown by 7th day from the beginning of administration of drug, in the first week additional non-hormonal methods of contraception are recommended.
Appointment is after the delivery recommended not earlier than there passes the first normal menstrual cycle.
Treatment needs to be stopped immediately in 3 months prior to the planned pregnancy and approximately in 6 weeks prior to the planned surgical intervention, at a long immobilization.
At diarrhea and vomiting the contraceptive effect decreases (without stopping administration of drug, it is necessary to use additional non-hormonal methods of contraception). The smoking women accepting hormonal contraceptive medicines have the increased risk of development of vascular diseases with serious effects (a myocardial infarction, a stroke). The risk increases with age and depending on quantity of the smoked cigarettes (especially at women 30 years are more senior).

Side effects:

From endocrine system: in rare instances - a nagrubaniye, morbidity, increase and allocations from mammary glands, increase in body weight.
From a reproductive system: in rare instances - intermenstrual bleedings, changes of a vulval secret, change of a libido.
From TsNS: in rare instances - a headache, migraine, decrease in mood.
From the alimentary system: in rare instances - nausea, vomiting, a gastralgia,
Others: seldom or never - bad portability of contact lenses, the century, a vision disorder, conjunctivitis, decrease in hearing, allergic reactions, thrombophlebitis, a thrombembolia, a generalized itch, jaundice, emergence of a nevus pigmentosus on a face (hloazm) swelled.
The listed side effects can develop in the first several months of reception ХЛОЕ® and usually decrease over time.

Interaction with other medicines:

At simultaneous use ХЛОЕ® with inductors of microsomal liver enzymes (hydantoins, barbiturates, Primidonum, carbamazepine and rifampicin; and also, perhaps, with okskarbazepiny, topiramaty, felbamaty and griseofulvin) the clearance of ethinylestradiol and a tsiproteron increases that can lead to breakthrough uterine bleedings or decrease in reliability of contraception.
At simultaneous use with ampicillin, rifampicin and tetracyclines contraceptive reliability ХЛОЕ® decreases.

Contraindications:

• fibrinferments and thromboembolisms, including in the anamnesis (deep vein thrombosis, a thromboembolism of a pulmonary artery, a myocardial infarction, cerebrovascular disturbances);
• the states preceding thrombosis (including the tranzitorny ischemic attacks, stenocardia);
• arterial hypertension;
• the diabetes mellitus complicated by mikroangiopatiya;
• existence of heavy or multiple factors of risk of venous or arterial thrombosis;
• diseases or the expressed abnormal liver functions;
• liver tumors (including in the anamnesis);
• hormonedependent malignant tumors, including tumors of a mammary gland or generative organs (including in the anamnesis);
• uterine bleedings of not clear etiology;
• pancreatitis (including in the anamnesis) if it was followed by a heavy gipertriglitseridemiya;
• existence in the anamnesis of migraine which was followed by focal neurologic symptomatology;
• lactation;
• pregnancy or suspicion on it;
• inborn hyperbilirubinemias (Gilbert's syndromes, Cudgel Johnson and Rotor);
• sickemia;
• idiopathic jaundice or an itch during the former pregnancy;
• an otosclerosis with deterioration during pregnancy;
• the age is more senior than 40 years;
• giperprolaktinemiya;
• hypersensitivity to drug components.
If any of these states develop for the first time against the background of reception ХЛОЕ®, drug has to be immediately cancelled.
With care - epilepsy, a depression, ulcer colitis, diseases of a liver and a gall bladder, a hysteromyoma, a mastopathy, a chorea, a tetany, a porphyria, multiple sclerosis, a varicosity, tuberculosis, diseases of kidneys, teenage age (without regular ovulatory cycles).

Overdose:

Symptoms: nausea, vomiting, small vulval bleeding. Treatment: carry out symptomatic therapy. There is no specific antidote.

Storage conditions:

To store at a temperature not above 25 °C in the place, unavailable to children! Period of validity 3 years.

Issue conditions:

According to the recipe

Packaging:

Tablets are film coated. On 21 tablets of yellow-orange color, film coated together with 7 tablets of white color (placebo) in the blister from PVH/A1. On 1 or 3 blisters are placed in a cardboard pack together with the application instruction.