Euro

General characteristics. Structure:

Each plaster transdermalny contains 6 mg of a norelgestromin (NG) and 600 mkg of ethinylestradiol (EE).

Each plaster during 24 h allocates 203 mkg of NG and 33,9 mkg of EE.

The plaster transdermalny consists of the following layers:

Excipients: adhesive mix of polyisobutylene and polybutylene – 221,4 mg, a lauryllactate – 12 mg, кросповидон – 60 mg.

Nonwoven fabric from polyester – 34 mg, the supporting film – 110,70 mg, a protective film – 208,95 mg.

Description. A square plaster transdermalny with a beige opaque substrate, the rounded-off corners, perforation in the area of a separation, a colourless glue (adhesive) layer and a transparent protective film. On a substrate the text of "EVRA" is squeezed out. The size of a plaster of transdermalny Evra on length and width (together with a protective film) makes (51,0+1,0) mm x (51,0+1,0) mm.

Pharmacological properties:

Pharmacodynamics. Oppresses gonadotropic function of a hypophysis, suppresses development of a follicle and interferes with process of an ovulation. The contraceptive effect also amplifies due to increase in viscosity of a secret of a neck of uterus and decrease in a susceptibility of an endometria to a blastocyste. Perl (0,90) index reflects the frequency of approach of pregnancy at 100 women within 12 months of use of the chosen contraception method.

Frequency of approach of pregnancy does not depend on age, race, but more than 90 kg increase at women with body weight.

Pharmacokinetics. Absorption. Concentration of a norelgestromin and ethinylestradiol in a blood plasma reach stationary values in 48 hours after application of a plaster of transdermalny Evra® and make 0,8 ng/ml and 50 pg/ml respectively.

At long use of a plaster of transdermalny Evra® equilibrium concentration (Css) and the area under a curve "concentration time" (AUC) increase a little. At various temperature conditions and an exercise stress there are no significant changes of Css and AUC of a norelgestromin, and ethinylestradiol AUC increases a little at an exercise stress whereas Css remains invariable.

Target Css values of a norelgestromin and ethinylestradiol are maintained for 10 days of use of a plaster of transdermalny Evra®, i.e. clinical performance of a plaster transdermalny can remain even if the woman will make its next replacement for 2 full days after the planned seven-day term.

Distribution. Norelgestromin and Norgestrelum (a serumal metabolite of a norelgestromin) possess high degree (> 97%) linkng with proteins of plasma. Norelgestromin contacts albumine, Norgestrelum contacts preferential the globulins connecting sex hormones. Ethinylestradiol possesses high extent of linkng with blood plasma albumine.

Biotransformation. Norelgestromin is metabolized in a liver, with formation of a metabolite of Norgestrelum, and also various hydroxylated and conjugated metabolites. Ethinylestradiol is metabolized before various hydroxylated connections and their glyukuronidny and sulphatic conjugates. Progestogens and estrogen inhibit many enzymes of system of R-450 cytochrome (including CYP 3A4, CYP 2C19) in microsomes of a liver of the person.

Elimination. The average elimination half-life of a norelgestromin and ethinylestradiol makes about 28 and 17 h respectively. Metabolites of a norelgestromin and ethinylestradiol eliminirutsya by kidneys and through intestines.

Influence of age, body weight and surface area of a body. Css and AUC values of a norelgestromin and ethinylestradiol slightly decrease with increase in age, body weight or surface area of a body.

Indications to use:

Contraception at women. 

Route of administration and doses:

Dose.

Nakozhno. Have to apply a plaster to achievement of the maximum contraceptive effect of the woman transdermalny Evra® in strict accordance with instructions. The instructions concerning the beginning of use of a plaster of transdermalny Evra® are given below in the section "How to Begin Use of a Plaster of Transdermalny Evra®\". It is at the same time possible to apply only one plaster transdermalny Evra®.

Each used plaster transdermalny Evra® is deleted and at once replaced new in the same day of the week ("day of replacement") for the 8th and 15th days of a cycle of use of drug (the 2nd and 3rd week). A plaster transdermalny Evra® it is possible to change replacements at any time. Within the 4th week, from the 22nd to the 28th day of a cycle, the plaster transdermalny Evra® is not used.

The new contraceptive cycle begins next day after the termination of the 4th week; the following plaster transdermalny Evra® should be pasted even if menstrualnopodobny bleeding of "cancellation" was not or it did not end.

Having under no circumstances rummaged in carrying a plaster of transdermalny Evra® there should not be more than 7 days, otherwise the risk of approach of pregnancy increases. In such situations for 7 days it is necessary to use at the same time a barrier method of contraception as the risk of an ovulation increases every day of exceeding of the recommended duration of the period, free from use of a plaster of transdermalny Evra®. In case of sexual contact during such increased period the probability of conception is very high.

Route of administration.

The plaster transdermalny Evra® should be pasted on clean, dry, intact and healthy skin of buttocks, a stomach, an outside surface of an upper part of a shoulder or an upper part of a trunk with the minimum pilosis, on sites where it will not adjoin to skintight clothes.

In order to avoid possible irritation each following plaster transdermalny Evra® needs to be pasted on other site of skin, it can be done within the same anatomic area. Use of a plaster transdermalny on area of mammary glands is inadmissible.

The plaster transdermalny Evra® needs to be pressed densely that its edges well adjoined to skin. For prevention of decrease in adhesive properties of a plaster of transdermalny Evra® it is impossible to do a make-up, creams, lotions, powders and other local funds for those sites of skin where it is pasted or it will be pasted.

The woman has to examine daily a plaster transdermalny Evra® to be confident in its strong attachment.

The used plaster transdermalny needs to be utilized accurately according to recommendations.

Recommendations about utilization.

As the used plaster transdermalny contains significant amounts of active ingredients, it should be utilized accurately. For this purpose separate a special cling film from the outer side of a bag. Place the used plaster transdermalny in a bag so that its sticky party was turned to the painted zone on a bag, and slightly press for sticking up. The stuck bag is thrown out. The used plaster transdermalny cannot be thrown into a toilet bowl or into the sewerage.

How to begin use of a plaster of transdermalny Evra®.

If during the previous menstrual cycle the woman did not apply a hormonal contraceptive. Contraception by means of a plaster of transdermalny Evra® is begun in the first day of periods. Paste to skin one plaster transdermalny Evra® and use it all week (7 days). Day of gluing of the first plaster of transdermalny Evra® (the 1st day/day of the beginning) defines the next days of replacement. Day of replacement will fall on the same day every week (the 8th and 15th days of a cycle). For the 22nd day of a cycle the plaster transdermalny is removed, and from the 22nd to the 28th day of a cycle the woman does not use plastyrtransdermalny Evra®. The next day is considered in the first afternoon of a new contraceptive cycle.

If the woman begins use of a plaster of transdermalny Evra® not from the first day of periods, then it is necessary to use at the same time barrier methods of contraception within 7 first days of the first contraceptive cycle.

If the woman passes from the combined peroral contraceptive drug to use of a plaster of transdermalny Evra®. The plaster transdermalny Evra® should be pasted on skin in the first day of the menstrualnopodobny bleeding of "cancellation" which began later the terminations of reception of the combined oral contraceptive. If menstrualnopodobny bleeding does not begin within 5 days after reception of a contraceptive tablet, then it is necessary to exclude pregnancy before beginning use of a plaster of transdermalny Evra®. If use of Evra® begins after the first day of menstrualnopodobny bleeding, then within 7 days it is necessary to use barrier methods of contraception at the same time. If after reception of the last contraceptive tablet there passed more than 7 days, then the woman can have an ovulation and therefore she has to consult with the doctor before beginning to apply a plaster transdermalny Evra®. The sexual contact during this increased period, free from reception of contraceptive tablets, can lead to pregnancy approach.

If the woman passes from the contraceptive drugs containing only progestogen to use of a plaster of transdermalny Evra®. The woman can pass in any day from use of the drug containing only progestogen (in day of removal of an implant, in day when the next injection has to be made), but during the first 7 days of use of a plaster of transdermalny Evra® it is necessary to use a barrier method for strengthening of contraceptive effect.

After abortion or an abortion.

After abortion or an abortion till 20th week of pregnancy it is possible to begin use of a plaster of transdermalny Evra® at once. If the woman begins to apply a plaster transdermalny Evra® at once after abortion or an abortion, it is not required to resort to an additional method of contraception. The woman has to know that the ovulation can occur within 10 days after abortion or an abortion. After abortion or an abortion on the 20th week of pregnancy or late use of a plaster of transdermalny Evra® it is possible to begin for the 21st day after abortion or an abortion, or in the first day of the first come periods (depending on what will come earlier).

After the delivery.

The women who are not nursing the child can begin use of a plaster of transdermalny Evra® not earlier than in 4 weeks after the delivery. If the woman begins to apply a plaster transdermalny Evra® later, then during the first 7 days she has to use a barrier method of contraception in addition. If the sexual contact took place, then it is necessary to exclude pregnancy before beginning use of a plaster of transdermalny Evra®, or the woman has to wait for the first periods.

At full or partial unsticking of a plaster of transdermalny Evra®.

If the plaster transdermalny Evra® in whole or in part came unstuck, then the insufficient amount of its active ingredients comes to blood.

Even at partial unsticking of a plaster of transdermalny Evra®:

• less than within a day (to 24 h): it is necessary to paste again a plaster transdermalny Evra® on the same place or at once to replace it with a new plaster transdermalny Evra®. Additional contraceptives are not required. The following plaster трансдермальныйЕвра® needs to be pasted in usual "day of replacement".

• more than within a day (24 h and longer) and also if the woman does not know precisely when the plaster transdermalny Evra® partially or completely came unstuck: pregnancy approach is possible. The woman has to begin at once a new cycle, having pasted a new plaster transdermalny Evra® and to consider this day in the first afternoon of a contraceptive cycle. Barrier methods of contraception should be applied at the same time only in the first 7 days of a new cycle.

It is not necessary to try to paste again a plaster transdermalny Evra® if it lost the adhesive properties; instead it is necessary to paste at once a new plaster transdermalny Evra®. It is impossible to apply additional adhesive tapes or bandages to deduction on site of a plaster of transdermalny Evra®.

If the next days of replacement of a plaster of transdermalny Evra® are missed.

At the beginning of any contraceptive cycle (the 1st неделя/1st-y day): At the increased risk of emergence of pregnancy the woman has to paste the first plaster transdermalny Evra® of a new cycle at once as soon as remembers it. This day is considered new "in the 1st afternoon" and new "day of replacement" is counted. Barrier methods of contraception should be applied at the same time during the first 7 days of a new cycle. In case of sexual contact during the extended period without use of contraception there can be a conception.

In the middle of a cycle (the 2 неделя/8th-y day or the 3 неделя/15th-y day):

• from the date of replacement one passed or two days (to 48 h): the woman has to paste at once a new plaster transdermalny Evra®. The following plaster transdermalny Evra® needs to be pasted in usual "day of replacement". If within 7 days preceding the first missed day of an attachment of a plaster of transdermalny Evra®, the woman correctly applied a plaster transdermalny Evra®, then additional contraception is not required;

• from the date of replacement there passed more than two days (48 h and more): there is an increased risk of emergence of pregnancy. The woman has to stop the current contraceptive cycle and at once begin a new 4 weeks cycle, having pasted a new plaster transdermalny Evra®. This day is considered new "in the 1st afternoon" and new "day of replacement" is counted. Barrier contraception should be applied at the same time within 7 first days of a new cycle;

• at the end of a cycle (the 4 неделя/22nd-y day): if the plaster transdermalny Evra® is not removed at the beginning of the 4th week (the 22nd day), then it needs to be removed as soon as possible. The next cycle of contraception has to begin in usual "day of replacement" which is the next day after the 28th day. Additional contraception is not required.

Change of day of replacement. If the woman considers necessary transfer of day of replacement, the current cycle has to be complete. Removal of the third plaster of transdermalny Evra® has to be made in usual day of replacement. During a week, free from use, the woman can choose new day of replacement, having pasted the first plaster transdermalny Evra® of the following cycle in the chosen day. The period, free from use of a plaster of transdermalny Evra®, should not be more than 7 days at all. The this period is shorter, the probability that the woman will have no next menstrualnopodobny bleeding is higher, and during the following contraceptive cycle there can be acyclic plentiful or scanty bloody allocations.

Features of use:

Before use of a plaster of transdermalny Evra® it is necessary to collect the detailed medical anamnesis concerning the immediate family, including data on heredity and to exclude pregnancy. It is necessary to carry out the general (including measurement of arterial pressure, inspection of mammary glands, mammography) and gynecologic inspection. At suspicion on genetic predisposition to a venous thromboembolism (in the presence of a venous thromboembolism at the brother, the sister or at parents), the woman should be directed to consultation to the specialist.

At purpose of a plaster of transdermalny Evra® it is necessary to take into account probability of emergence of tromboembolic episodes (thrombophlebitises, venous thromboembolisms, including an embolism of a pulmonary artery, tserebralnovaskulyarny diseases and thrombosis of vessels of a retina of an eye). At the slightest manifestation of symptoms any of these diseases, use of a plaster of transdermalny Evra® has to be immediately stopped. It was conducted several epidemiological researches of the venous thromboembolisms (VTE) estimating risk of emergence among the women applying a plaster transdermalny Evra® in comparison with the women accepting various peroral contraceptive drugs. The probable index of emergence of VTE among the women applying a plaster transdermalny Evra® varied from 0,9 (the risk does not increase) to 2,4 (the risk increases by 2,4 times).

The risk of vascular complications is increased at women with thrombophlebitis of superficial veins and with a varicosity, and also at obesity (an index of body weight more than 30 kg/sq.m).

Conditions of a long immobilization or operative measures on the lower extremities, obesity or existence in the family anamnesis of tromboembolic episodes are capable to increase risk of development of venous tromboembolic episodes. In this regard it is recommended to stop use of hormonal contraceptives in 4 weeks prior to an operative measure (at planned operation) and within two weeks after the carried-out emergency operative measure, and also during and after a long immobilization.

Some epidemiological researches revealed the increased risk of development of a breast cancer at prolonged use of the combined hormonal contraceptives especially at young age, before the first pregnancy. In some researches it is shown that reception of hormonal contraceptives is connected with increase in risk of development of tumors of a neck of uterus, including cancer.

The women applying the combined contraceptives can have benign adenomas of a liver which can be the cause of life-threatening intra belly bleedings. The risk of their emergence increases after the 4th and more years of use.

In case of developing of severe pains in an upper half of a stomach, increase in a liver or symptoms of intra belly bleeding, it is necessary to carry out differential diagnosis for a liver tumor exception.

At emergence pharmacological uncontrollable arterial hypertension at women during use of the combined hormonal contraceptives should cancel drug, use of a plaster transdermalny can be resumed after normalization of arterial pressure.

Hormonal contraceptives can influence certain indicators of functional tests of hemadens, markers of function of a liver and components of blood:

- concentration of a prothrombin and factors of coagulation of VII, VIII, IX and X increase; antithrombin III levels decrease; S protein levels decrease; aggregation of thrombocytes amplifies;

- content of tiroksinsvyazyvayushchy globulin increases that causes increase in concentration of the general thyroid hormone. Binding of free triiodothyronine (T3) ion-exchange resin decreases what increase in concentration of tiroksinsvyazyvayushchy globulin testifies to, concentration of free thyroxine (T4) does not change;

- in plasma levels of other connecting proteins can be increased;

- concentration of the globulins connecting sex hormones that leads to increase in concentration of the general circulating endogenous sex hormones increase. At the same time, concentration of free or biologically active sex hormones decrease or remain invariable;

- concentration of cholesterol of lipoproteins of the high density (H-LPVP), the general cholesterol, cholesterol of lipoproteins of the low density (H-LPNP) and triglycerides whereas the ratio of H-LPNP/H-LPVP can remain invariable increase;

- tolerance to glucose decreases;

- concentration of serumal folates decrease that can soon have potentially clinically significant effects in case of pregnancy of postcancellation of a hormonal contraceptive. Now all women informed on the deficit of folic acid which is available for them are recommended to accept it on early duration of gestation.

The combined hormonal contraceptives can influence resistance of peripheral fabrics to insulin and on tolerance to glucose, however there are no proofs of need to change the mode of therapy of a diabetes mellitus during use of the combined hormonal contraceptives. At the same time, it is necessary to watch attentively the state of health of women with a diabetes mellitus, especially at an early stage of use of a plaster of transdermalny Evra®.

− there are clinical observations about cases of thrombosis of vessels of a retina of the eye tied using hormonal contraceptives. Reception of oral contraceptives has to be stopped in case of unexpected tranzitorny, partial or total loss of sight; attacks of a zamutneniye of sight or diplopia; hypostasis of a nipple or disturbance of integrity of vessels of a retina. The relevant diagnostic and therapeutic activities have to be undertaken immediately.

− Hloazma: women at whom the face skin hyperpegmentation was observed during pregnancy have to avoid influence of solar or artificial ultra-violet light during use of a plaster of transdermalny Evra® as such hyperpegmentation happens not completely reversible.

Women should be informed that the plaster does not protect transdermalny Evra® from HIV infection (AIDS) and other diseases, sexually transmitted.

At use of the combined hormonal contraceptives emergence of the smearing bloody allocations, especially in the first 3 months of contraception is possible.

If in cases of prolonged use of a plaster of transdermalny Evra® according to recommendations acyclic bloody allocations are observed for a long time or such allocations arise after the previous regular cycles, then it is necessary to consider other reasons, in addition to use of a plaster transdermalny. It is necessary to remember non-hormonal causes of infringement of a cycle of use of drug and more carefully to inspect the woman for an exception of organic diseases and pregnancy.

Absence of menstrualnopodobny bleeding of "cancellation" at some women during the period, free from use of a plaster of transdermalny Evra® is possible. If the woman violated instructions on use during the period preceding the first cancelled menstrualnopodobny bleeding of "cancellation" or if it had no two menstrualnopodobny bleedings of "cancellation" after breaks of use of a plaster transdermalny, then it is necessary to exclude pregnancy before continuing use of a plaster of transdermalny Evra®.

At some women cancellation of hormonal contraceptives can provoke absence of menstrualnopodobny bleeding of "cancellation" or rare menstrualnopodobny bleedings, especially at their existence prior to hormonal contraception. If use of a plaster of transdermalny Evra® causes irritation of skin, then it is possible to paste a new plaster transdermalny Evra® on other site of skin and to carry it till next day replacements. It is at the same time possible to use only one plaster transdermalny.

The plaster transdermalny Evra® cannot be damaged or cut. If the plaster transdermalny Evra® is damaged (the form is changed, a part of a plaster transdermalny is cut off or there are other visible damages), then efficiency of contraceptive action can decrease.

Women with body weight have 90 kg or more efficiency of contraception can be reduced. Smoking during use of a plaster of transdermalny Evra® increases risk of emergence of side effects from cardiovascular system (see the section "Side effects"). To the women applying a plaster transdermalny Evra® it is strongly recommended to abstain from smoking.

Safety and efficiency of a plaster of transdermalny Evra® are established only for women of 18 years before a menopause.

During use of a plaster of transdermalny Evra® women need to have regular routine medical examinations. Frequency and volume of these surveys have to be based on the corresponding instructions, and also have to be individually chosen for each woman on the basis of a clinical picture, but at least 1 time in six months.

Influence on ability to control of vehicles and mechanisms. The plaster transdermalny Evra® does not influence or slightly influences ability to driving and other mechanisms.

Side effects:

− unpleasant feelings in mammary glands, a headache, reactions in the place of use and nausea were the Most frequent side effects observed in clinical tests. Reactions in the place of use, unpleasant feelings in mammary glands (including a sensation of discomfort and mammary gland pain, swelling of mammary glands), nausea, a headache and emotional instability were the most frequent side effects which led to refusal of use of a plaster of transdermalny Evra®. Also during clinical trials the following side effects revealed less than at one percent of patients were observed: galactorrhoea, symptom complex similar to a premenstrual syndrome, changes of vulval secretion, insomnia, change of a libido.

− the Frequency of undesirable effects was classified as follows:

− It is very frequent ≥ 1/10;

− it is frequent ≥ 1/100 and <1/10;

− Infrequently ≥ 1/1000 and <1/100;

− it is rare ≥ 1/10000 and <1/1000;

− It is very rare <1/10000, including separate messages.

The following undesirable effects were noted:

The general disturbances and reactions in the place of use:

Often: skin reactions in the place of use (burning, dryness, hems, hematomas, a photosensitivity, a peeling, swelling, crusting, paresthesia, bleeding, an inflammation, consolidation, an atrophy, excoriation, an anesthesia, infection, an ulcer, eczema, nodulation, pustules, allocations, abscess, tumorous growth, an erosion, an unpleasant smell), fatigue, an indisposition.

Infrequently: irritation, peripheral hypostases, hypersensitivity;

Disturbances from the central and peripheral nervous system:

Very often: headache;

Often: dizziness, migraine;

Very seldom: disturbances of cerebral circulation (including passing disturbances of cerebral circulation; ischemic and hemorrhagic strokes, occlusions and stenoses of vessels of a brain), migraine with focal neurologic symptomatology, subarachnoidal hemorrhage, a dysgeusia.

Disturbances from cardiovascular system:

Infrequently: arterial hypertension;

Seldom: venous fibrinferments; thrombophlebitis of veins of extremities;

Very seldom: myocardial infarction, arterial thromboses and thromboembolisms, hypertensive crisis.

Disturbances from digestive tract:

Very often: nausea;

Often: abdominal pain, vomiting, diarrhea, abdominal distention;

Very seldom: colitis.

Disturbances from reproductive system and mammary glands:

Very often: a sensation of discomfort in mammary glands, increase in a mammary gland, swelling, pain, puffiness, increase in sensitivity, fibrous and cystous changes of mammary glands;

Often: painful bleeding of "cancellation", uterus spasm, vulval allocations;

Infrequently: tumors of a mammary gland, a galactorrhoea, dryness of a mucous membrane of a vagina and vulva, allocation from a genital tract;

Seldom: absence of menstrualnopodobny bleeding, rare menstrualnopodobny bleedings;

Very seldom: cervical dysplasia, scanty/plentiful menstrualnopodobny bleedings, acyclic bleedings, suppression of a lactation.

Disturbances from skin and hypodermic fabrics:

Often: itch, skin reactions, eels;

Infrequently: alopecia, allergic dermatitis, erythema, hloazma, eczema, photosensitivity reactions, small tortoiseshell;

Seldom: generalized itch, erythematic rashes, pruritic rash;

Very seldom: Quincke's disease, poliformny, knotty erythema, exfoliative rash, seborrheal dermatitis.

Disturbances from a metabolism and food:

Often: increase in body weight;

Very seldom: a hyperglycemia, increase in appetite, resistance to insulin.

Gepatobiliarny disturbances:

Infrequently: cholelithiasis, cholecystitis;

Very seldom: cholestasia, damages of a liver, cholestatic jaundice.

Disturbances from organs of sight:

Very seldom: intolerance of contact lenses.

Mental disturbances:

Often: emotional instability, uneasiness, affect, aggression, depression, tearfulness;

Infrequently: sleeplessness, change of a libido;

Very seldom: anger, frustration.

New growths are high-quality, malignant and an uncertain etiology (including cysts and polyps):

Seldom: uterus leiomyoma;

Very seldom: breast cancer, cancer of a neck of uterus, fibroadenoma of a mammary gland, adenoma of a liver, liver new growth.

From a musculoskeletal system:

Often: muscular spasms.

Infections and invasions:

Often: fungal infections of a vagina;

Very seldom: pustular rashes.

Change of laboratory indicators:

Very seldom: change of concentration of cholesterol in blood, change of concentration of glucose in blood, increase in concentration of lipoproteins of low density.

Interaction with other medicines:

The changes of efficiency of contraception connected with combined use of a plaster of transdermalny Evra® with other drugs.

If the woman applying a plaster transdermalny Evra® accepts medicine or medicine of a plant origin which induce microsomal enzymes of a liver (except for rifampicin), including CYP3A4 metabolizing contraceptive hormones she should be warned about need of use of means of additional contraception or other method of contraception during all reception of such medicines, and also within 7 days after its termination. The women accepting rifampicin have to use a barrier method of contraception in addition to a plaster to transdermalny Evra® during the whole time of reception of rifampicin, and also within 28 days after its termination. The women accepting antibiotics (except for rifampicin), have to use a barrier method of contraception up to the 7th day after cancellation of their reception. At long therapy by these drugs more than 3 weeks, the new contraceptive cycle begins at once, without the usual period, free from use.

Medicines or medicines of a plant origin which induce microsomal enzymes of a liver reduce concentration of contraceptive hormones in a blood plasma and can reduce efficiency of a plaster of transdermalny Evra® or cause acyclic bleeding. Treat some drugs or medicines of a plant origin which can reduce efficiency of hormonal contraceptives:

• some antiepileptic drugs (for example, carbamazepine, eslikarbazepin acetate, фелбамат, окскарбазепин, Phenytoinum, руфинамид, топирамат);

• (фос) aprepitant;

• barbiturates;

• бозентан;

• griseofulvin;

• some of inhibitors of HIV protease or their combinations (for example, нелфинавир, ритонавир, the protease inhibitors strengthened ritonaviry);

• modafinit;

• some nenukleozidny inhibitors of the return transcriptase (for example, not Virapinum);

• rifampicin and рифабутин;

• drugs of the St. John's Wort which is made a hole.

The inducing effect can remain within 4 weeks after cancellation of the vegetable drug containing the St. John's Wort which is made a hole. Inhibitors of HIV protease and nukleozidny inhibitors of the HIV return transcriptase: in certain cases at combined use of inhibitors of HIV protease and nukleozidny inhibitors of the HIV return transcriptase noted significant changes (increase or decrease) of levels of estrogen and progestin in a blood plasma.

Antibiotics: there are messages on cases of approach of pregnancy at use of hormonal contraceptives and antibiotics, but during pharmacokinetic clinical trials of significant impact of antibiotics on concentration of synthetic steroids in a blood plasma is not revealed. During the research of pharmacokinetic interaction of medicines peroral introduction of 500 mg of tetracycline of a hydrochloride 4 times a day in 3 days prior to use of a plaster of transdermalny Evra® and within 7 days after its use did not exert considerable impact on pharmacokinetics of a norelgestromin or ethinylestradiol.

The increase in level of hormones in a blood plasma connected with combined use of drugs. Some drugs and grapefruit juice can increase ethinylestradiol level in a blood plasma on condition of their joint introduction. Treat them:

• paracetamol;

• ascorbic acid;

• CYP3A4 inhibitors (including итраконазол, кетоконазол, вориконазол, флуконазол and nreypfrutovy juice);

• эторикоксиб;

• some inhibitors of HIV protease (for example, атазанавир, инданавир);

• inhibitors of HMG-CoA-reductase (including аторвастатин and розувастатин);

• some nenukleozidny inhibitors of the return transcriptase (for example, этравирин).

Changes of levels of the drugs administered together with contraceptives in a blood plasma.

The data obtained as a result of use of the oral combined hormonal contraceptives also indicate a possibility of their impact on pharmacokinetics of some other drugs on condition of their combined use. Treat drugs which levels in a blood plasma can be increased (in connection with CYP inhibition):

• cyclosporine;

• омепразол;

• Prednisolonum;

• селегилин;

• theophylline;

• тизанидин;

• вориконазол.

Drugs which levels in a blood plasma can be reduced (in connection with induction of a glyukuronirovaniye) include:

• paracetamol;

• Clofibratum;

• ламотриджин (see below);

• morphine;

• salicylic acid;

• temazepam.

Lamotridzhin: it became clear that probably in connection with induction of a glyukuronirovaniye of a lamotridzhin, the combined hormonal contraceptives considerably reduced concentration of a lamotridzhin in a blood plasma at joint administration of drugs. It can provoke an attack of spasms; correction of doses of a lamotridzhin is possible. It is recommended to consult doctors about marking jointly of the accepted drugs for the purpose of obtaining further information on their interaction with hormonal contraceptives or the potential of alteration of enzymes with possible need of dose adjustment.

Contraindications:

The plaster transdermalny Evra® is contraindicated at women at the following states:

• fibrinferments (arterial and venous) and thromboembolisms now or in the anamnesis (including, thrombosis, thrombophlebitis of deep veins; thromboembolism of a pulmonary artery, myocardial infarction, stroke, cerebrovascular disturbances);

• the states preceding thrombosis (including, the tranzitorny ischemic attacks, stenocardia) now or in the anamnesis;

• genetic predisposition to venous or arterial thrombosis, including resistance of the activated protein With, deficit of antithrombin III, deficit of a protein With, deficit of a protein of S, a gipergomotsisteinemiya, existence of antibodies to phospholipids (antibodies to cardiolipin, lupoid anticoagulant), etc.;

• the multiple or expressed risk factors of venous or arterial thrombosis, including the complicated defeats of the valve device of heart, a subacute bacterial endocarditis, fibrillation of auricles, diseases of vessels of a brain or coronary arteries, uncontrollable arterial hypertension, smoking are aged more senior than 35 years, a hereditary dislipoproteinemiya, volume surgical intervention with a long immobilization, obesity (the index of body weight more than 30 kg/sq.m calculated as the body weight relation in kilograms to growth square in meters);

• a diabetes mellitus with defeat of vessels;

• migraine with focal neurologic symptomatology;

• the confirmed or suspected breast cancer;

• diagnosed (including, in the anamnesis) estrogenzavisimy malignant tumors (for example, endometrial cancer) or suspicion of them;

• bleeding from a vagina of the obscure etiology;

• cholestatic jaundice during pregnancy or jaundice when using hormonal contraceptives earlier;

• an acute or chronic disease of a liver with an abnormal liver function;

• benign or malignant tumors of a liver;

• puerperal period (4 weeks);

• known or alleged pregnancy;

• lactation period;

• hypersensitivity to drug components;

• age up to 18 years.

With care:

- a venous or arterial thromboembolism at brothers, sisters or at parents at rather young age;

- thrombophlebitis of superficial veins and varicosity;

- controlled arterial hypertension;

- heavy migraine without focal neurologic symptomatology;

- a diabetes mellitus without vascular complications;

- existing (or in the anamnesis) a heavy depression;

- existing (or in the anamnesis) cholelithiasis;

- chronic idiopathic jaundice;

- cholestatic jaundice in the family anamnesis (for example Rotor syndromes, the Cudgel - Johnson);

- an acute disorder of function of a liver during the previous pregnancy or the previous use of sex hormones;

- system lupus erythematosus;

- ulcer colitis;

- disease Krone;

- gipertriglitserilemiya;

- gemolitiko-uraemic syndrome;

- Sydenham's chorea;

- porphyria;

- herpes during pregnancy;

- otosclerosis;

- multiple sclerosis;

- hloazma;

- hysteromyoma and endometriosis;

- presence of relatives of the 1st line of relationship with a breast cancer.

Overdose:

Symptoms: nausea, vomiting, bleedings from a vagina. Treatment: there is no specific antidote. It is necessary to remove a plaster transdermalny and to carry out symptomatic therapy.

Storage conditions:

At a temperature not above 30 °C. To store in original packaging. To store in the place unavailable to children.

Issue conditions:

According to the recipe

Packaging:

The plaster is transdermalny, 6 mg of a norelgestromin (NG) and 600 mkg of ethinylestradiol (EE); on one plaster transdermalny in a package from the laminated paper and aluminum foil, on 3 packages are together laid in a transparent package from a polymeric film. On the 3 or 9 plaster transdermalny (1 or 3 packages) in a cardboard pack together with the application instruction and special stickers on a calendar for a mark of term of use of a plaster transdermalny.