Consequences of long-term use of Diana 35. Medicinal reference book geotar

Active substances: cyproterone acetate 2 mg and ethinyl estradiol 0.035 mg.
Excipients: lactose monohydrate - 31.115 mg, corn starch
- 18.000 mg, povidone - 2.100 mg, talc - 1.650 mg, magnesium stearate - 0.100 mg.
shell composition: sucrose - 19.371 mg, povidone 700000 - 0.189 mg, polyethylene glycol (macrogol 6000) - 2.148 mg, calcium carbonate - 8.606 mg, talc
- 4.198 mg, glycerol - 0.137 mg, titanium dioxide - 0.274 mg, iron (II) oxide yellow - 0.027 mg, mountain glycol wax - 0.050 mg.

Description. Round biconvex dragees of light yellow color.

Pharmacodynamics. Diane-35 is a low-dose monophasic oral combined estrogen-antiandrogen contraceptive drug.
The contraceptive effect of Diane-35 is carried out through complementary mechanisms, the most important of which include the suppression of ovulation and the change in the properties of the cervical secret, as a result of which it becomes impermeable to spermatozoa.
In women taking combined oral contraceptives, the menstrual cycle becomes more regular, painful periods are less common, intensity decreases, resulting in a reduced risk. In addition, there is evidence that the risk of developing and is reduced.
Against the background of taking Diane-35, increased activity decreases sebaceous glands, which plays an important role in the occurrence of acne and seborrhea. After 3-4 months of therapy, this usually leads to the disappearance of the existing rash. Excessive oiliness of hair and skin disappears even earlier. It also reduces hair loss, which often accompanies seborrhea. Diane-35 therapy in women reproductive age reduces clinical manifestations mild forms of hirsutism (particularly increased facial hair growth); however, the effect of the treatment should be expected only after several months of use.
Along with the antiandrogenic effect described above, cyproterone acetate also has a pronounced progestogenic effect.

Pharmacokinetics. . Cyproterone acetate
Absorption. When administered orally, cyproterone acetate is completely absorbed over a wide dose range. After ingestion of Diane-35 dragees, the maximum concentration (Cmax) of cyproterone acetate in serum, 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 binds exclusively to serum albumin. In the free form is only about 3.5-4% of the total concentration of blood serum. The increase in SHBG induced by ethinylestradiol does not affect the binding of cyproterone acetate to serum proteins. The average apparent volume of distribution is 986 ± 437 l

Metabolism. Cyproterone acetate is metabolized in two ways, including hydroxylation and conjugation. The main metabolite in human plasma is the 15P-hydroxyl derivative.
Withdrawal. Some of the dose is excreted unchanged in the bile. Most of the dose is excreted as metabolites in the urine or bile in a ratio of 1:2. Metabolites are eliminated from plasma with a half-life of 1.8 days.
equilibrium concentration. Since protein binding is not specific, changes in the level of sex steroid-binding globulin (SHBG) do not affect the pharmacokinetics of cyproterone acetate. During cycle treatment, the maximum equilibrium concentration of cyproterone acetate in serum is reached in the second half of the cycle.

Ethinylestradiol
Absorption. After oral administration, ethinylestradiol is rapidly and completely absorbed. The maximum concentration (Cmax) in the blood serum, equal to approximately 71 pg / ml, is reached in 1.6 hours. During absorption and the first passage through the liver, ethinyl estradiol is metabolized, as a result of which its oral bioavailability averages about 45%.
Distribution. Ethinyl estradiol is almost completely (approximately 98%), although non-specific, bound to albumin. Ethinylestradiol induces the synthesis of SHPS. The apparent volume of distribution of ethinylestradiol is 2.8-8.6 l / kg.
Metabolism. Ethinylestradiol undergoes presystemic conjugation both in the small intestine mucosa and in the liver. The main metabolic pathway is aromatic hydroxylation. The rate of clearance from blood plasma is 2.3-7 ml / min / kg.
Withdrawal. The decrease in the concentration of ethinylestradiol in the blood serum is biphasic; the first phase is characterized by a half-life of about 1 hour, the second - 10-20 hours. It is not excreted from the body unchanged. Metabolites of ethinylestradiol are excreted in the urine and bile in a ratio of 4:6 with an elimination half-life of about 24 hours.
equilibrium concentration. The equilibrium concentration is reached during the second half of the treatment cycle.

Contraception in women with androgenization phenomena.
Treatment of androgen-dependent diseases in women, such as especially common forms and forms accompanied by seborrhea, inflammation or nodule formation (papular-pustular acne, nodular cystic acne); and mild forms of hirsutism.

To achieve a therapeutic effect and provide the necessary contraception, Diane-35 should be taken regularly. If any other hormonal contraceptive drug was used before starting Diane-35, its intake should be discontinued. The dosing regimen for Diane-35 is the same as for most oral contraceptives. Thus, the rules for taking other oral contraceptives apply to Diane-35. Irregular intake of Diane-35 can lead to intermenstrual bleeding, a decrease in the therapeutic effect and contraceptive effectiveness. When applied correctly, the Pearl Index is approximately 1.
Dragee Diane-35 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 per day continuously for 21 days. The next pack is started after a 7-day break in taking the pills, during which withdrawal bleeding usually occurs. Bleeding usually starts 2-3 days after taking the last pill and may not end before starting a new pack.
How to start taking Diane-35
. In the absence of receiving any hormonal contraceptives in the previous month.
Reception Diane-35 begins on the first day of the menstrual cycle (i.e. on the first day of menstrual bleeding).
It is allowed to start taking it on the 2nd-5th day 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 taking the pills from the first package.
. When switching from other combined oral contraceptives, vaginal ring or a contraceptive patch.
It is preferable to start taking Diane-35 the next day after taking the last hormonal pill from the previous package, but in no case later than the next day after the usual 7-day break (for drugs containing 21 pills) or after taking the last inactive pill (for drugs containing 28 dragees per package).
Reception of Diane-35 should be started on the day of removal of the vaginal ring or patch, but no later than the day when a new ring is to be inserted or a new patch is pasted.
. When switching from contraceptives containing only gestagens ("mini-pill", injectable forms, implant), or from a progestogen-releasing intrauterine therapeutic system (Mirena).
You can switch from a mini-pill to Diana-35 on any day (without a break), from an implant or an intrauterine contraceptive with a progestogen - on the day it is removed, from an injection form - from the day the next injection is to be made. In all cases, it is necessary to use an additional barrier method of contraception during the first 7 days of taking the dragee.
. After an abortion in the first trimester of pregnancy.
A woman can start taking the drug immediately - on the day of the abortion. If this condition is met, the woman does not need additional contraceptive protection.
. After childbirth or abortion in the second trimester of pregnancy.
You should start taking the drug no earlier than 21-28 days after delivery in the absence of breastfeeding or after an abortion in the second trimester of pregnancy. If the reception is started later, it is necessary to use an additional barrier method of contraception during the first 7 days of taking the dragee. However, if a woman has already had a sexual life, before taking Diana-35, it is necessary to exclude pregnancy or wait for the first menstruation.
Taking missed pills
If the delay in taking the drug was less than 12 hours, contraceptive protection is not reduced. A woman should take the pill as soon as possible, the next one is taken at the usual time.
If the delay in taking the pill was more than 12 hours, contraceptive protection may be reduced. The more pills missed, and the closer the pass is to the 7-day break in taking pills, the greater the likelihood of pregnancy.
In this case, you can be guided by the following two basic rules:
. The drug should never be interrupted for more than 7 days.
. To achieve adequate suppression of the hypothalamic-pituitary-ovarian regulation, 7 days of continuous administration of the dragee are required.
Accordingly, the following advice can be given if the delay in taking the pill was more than 12 hours (the interval from the moment the last pill was taken was more than 36 hours):
. First week of taking the drug
The woman should take the last missed tablet as soon as she remembers (even if it means taking two tablets at the same time). The next dragee is taken at the usual time. Additionally, a barrier method of contraception (such as a condom) must be used for the next 7 days. If sexual intercourse took place within a week before skipping the dragee, the likelihood of pregnancy should be considered.
. Second week of taking the drug
The woman should take the last missed tablet as soon as she remembers (even if it means taking two tablets at the same time). The next dragee is taken at the usual time.
Provided that the woman has taken the pill correctly within 7 days preceding the first missed pill, there is no need to use additional contraceptive measures. Otherwise, as well as skipping two or more pills, you must additionally use barrier methods of contraception (for example, a condom) for 7 days.
. Third week of taking the drug
The risk of pregnancy is increased due to the upcoming break in taking the pill, however, if within 7 days preceding the first missed pill, all the pills were taken correctly, there is no need to use additional contraceptive methods.
1. The woman should take the last missed tablet as soon as she remembers (even if it means taking two tablets at the same time). The next pills are taken at the usual time until the pills from the current package run out. The next pack should be started immediately. Withdrawal bleeding is unlikely until the second pack is finished, but spotting and breakthrough bleeding may occur while taking the pills.
2. A woman can also stop taking the dragee from the current package. Then she should take a break for 7 days, including the day she skipped the dragee, and then start taking a new package.
If a woman misses taking the pills, and then during the break in taking she does not have withdrawal bleeding, pregnancy should be excluded.
Recommendations in case of vomiting and diarrhea
In case of vomiting or diarrhea up to 4 hours after taking the dragee, absorption may not be complete, and additional measures must be taken to prevent unwanted pregnancy. In such cases, you should be guided by the above recommendations when skipping dragees.
Changing the start date of the menstrual cycle
In order to delay the onset of menstruation, a woman should continue taking the pills from the new Diane-35 package immediately after taking all the pills from the previous one, without interrupting the intake. Dragees from this new package can be taken for as long as the woman wishes (until the package runs out). Against the background of taking the drug from the second package, a woman may experience spotting bloody issues or breakthrough uterine bleeding. Resume taking Diane-35 from a new pack should be after the usual 7-day break.
In order to move the day of the onset of menstruation to another day of the week, a woman should be advised to speed up the next break in taking dragees by as many days as she wants. The shorter the interval, the higher the risk that she will not have withdrawal bleeding and will have spotting and breakthrough bleeding during the second pack (as well as when she would like to delay the onset of her period.
Application duration
The duration of taking the dragee depends on the severity of the symptoms of androgenization and the response to treatment. Basically, the treatment is carried out for several months. The response to treatment for acne and seborrhea is usually faster than the response to treatment for hirsutism or alopecia.
It is recommended to take the drug for at least 3-4 courses after the disappearance of signs of the disease. In the event of a relapse of the disease a few weeks or months after stopping the pills, treatment with Diane-35 can be resumed. In the case of resumption of the drug (after a break of four weeks or more), an increased risk of VTE should be taken into account (see also the section "Special instructions" and "With caution").
Additional information for some patient groups
Children and teenagers.
The drug Diane-35 is indicated only after the onset of menarche. Elderly patients
Not applicable. Diane-35 is not indicated after menopause. Patients with liver disorders
Diane-35 is contraindicated in women with severe liver disease until liver function tests return to normal. See also section "Contraindications".
Patients with kidney disorders
Diane-35 has not been specifically studied in patients with renal impairment. Available data do not suggest a change in treatment in these patients.

If any of the conditions / risk factors listed below are currently present, then the potential risk and expected benefit of treatment with Diane-35 should be carefully weighed in each individual case and discussed with the woman before she decides to start taking the drug. If any of these conditions or risk factors worsen, worsen, or first appear, the woman should consult her physician, who may decide whether to discontinue the drug.
. Diseases of the cardiovascular system
There is evidence of an increase in the incidence of venous and arterial thrombosis and thromboembolism (such as myocardial infarction) when taking combined oral contraceptives.
The risk of developing venous thromboembolism (VTE) is highest in the first year of taking these drugs. An increased risk is present after the initial use of combined oral contraceptives or the resumption of use of the same or different combined oral contraceptives (after a break between doses of 4 weeks or more). Data from a large prospective study in 3 groups of patients show that this increased risk is present mainly during the first 3 months.
The overall risk of venous thromboembolism (VTE) in patients taking low-dose combined oral contraceptives (< 50 мкг этинилэстрадиола) в два-три раза выше, чем у пациентов, которые не принимают комбинированные пероральные контрацептивы, не беременны, и он остается более низким по сравнению с риском беременности и родов.
Very rarely, VTE can lead to disability or death.
Venous thromboembolism (VTE), manifesting as deep veins or pulmonary arteries, can occur with any combined oral contraceptive.
Very rarely, when using combined oral contraceptives, thrombosis of other blood vessels occurs, for example, veins or arteries of the liver, mesenteric, renal, brain or retina. There is no general opinion regarding the relationship between the occurrence of these events and the use of combined oral contraceptives.
Symptoms of deep vein thrombosis (DVT) include the following: unilateral swelling of the leg or along a vein in the leg, pain or tenderness in the leg only when standing or walking, feeling warm in the leg, redness or discoloration of the skin on the leg.
Symptoms of pulmonary embolism (PEA) are as follows: sudden unexplained or rapid breathing; sudden, including with blood; sharp pain in the chest, which may worsen with a deep breath; sense of anxiety; strong; fast or irregular heartbeat. Some of these symptoms (eg, "shortness of breath", "cough") are nonspecific and may be misinterpreted as signs of more or less severe events (eg, respiratory tract infection).
Arterial thromboembolism can lead to stroke, vascular occlusion, or myocardial infarction. The symptoms of a stroke are as follows: sudden weakness or loss of sensation in the face, arm or leg, especially on one side of the body, sudden confusion, problems with speech and understanding; sudden loss of vision in one or both eyes; sudden disturbance of gait, dizziness, loss of balance or coordination of movements; sudden, severe or prolonged for no apparent reason; loss of consciousness or fainting with or without an epileptic seizure. Other signs of vascular occlusion: sudden pain, swelling and slight bluing of the extremities, acute abdomen.
Symptoms of a myocardial infarction include: pain, discomfort, pressure, heaviness, a feeling of tightness or fullness in the chest, arm, or under the breastbone; discomfort with irradiation to the back, cheekbone, larynx, arm, stomach; cold sweat, or dizziness, severe weakness, or shortness of breath; fast or irregular heartbeat.
Arterial thromboembolism can be fatal.
The risk of thrombosis (venous and / or arterial) and thromboembolism increases:
. with age
. in smokers (with an increase in the number of cigarettes or an increase in age, the risk further increases, especially in women over 35 years old);
in the presence of:
. family history (i.e. venous or arterial thromboembolism ever in close relatives or parents at a relatively young age); in the case of a hereditary predisposition, the woman should be examined by an appropriate specialist to decide on the possibility of taking combined oral contraceptives;
. obesity (body mass index over 30 kg/m2);
. dyslipoproteinemia;
. arterial hypertension;
. migraine;
. heart valve disease;
. atrial fibrillation;
. prolonged immobilization, major surgery, any operation on the legs, or major trauma. In these situations, it is advisable to stop the use of combined oral contraceptives (in the case of a planned operation, at least four weeks before it) and not resume taking within two weeks after the end of immobilization.
Question about a possible role varicose veins veins and superficial in the development of venous thromboembolism remains controversial.
An increased risk of thromboembolism in the postpartum period should be taken into account.
Peripheral circulatory disorders can also be observed with diabetes, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease (Crohn's disease or) and.
An increase in frequency and severity during the use of combined oral contraceptives (which may precede cerebrovascular disorders) may be grounds for immediate discontinuation of these drugs.
Biochemical indicators indicating a hereditary or acquired predisposition to venous or arterial thrombosis include the following: resistance to activated protein C, antithrombin III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).
When evaluating the benefit/risk ratio, the clinician should consider that adequate treatment of the disease can reduce the associated risk of thrombosis and that the risk associated with pregnancy is higher than the risk associated with taking low-dose combined oral contraceptives (<0,05 мг этинилэстрадиола).
. Tumors
There are reports of some increased risk of developing the cervix with long-term use of combined oral contraceptives. The relationship with the use of combined oral contraceptives has not been proven. It remains a controversial question to what extent these findings are associated with the pathology of the cervix or with the characteristics of sexual behavior (more rare use of barrier methods of contraception). The most significant risk factor for development is persistent papillomavirus infection.
A meta-analysis of 54 epidemiological studies showed that there is a slightly increased relative risk of developing breast cancer diagnosed in women currently taking combined oral contraceptives (relative risk 1.24). The increased risk gradually disappears within 10 years after stopping these drugs.
Due to the fact that it is rare in women under 40 years of age, the increase in the number of breast cancer diagnoses in women currently taking combined oral contraceptives or who have recently taken it is insignificant in relation to the overall risk of this disease. Its relationship with the use of combined oral contraceptives has not been proven. The observed increase in risk may also be due to earlier diagnosis of breast cancer in women using combined oral contraceptives. In women who have ever used combined oral contraceptives, earlier stages of breast cancer are detected than in women who have never used them.
In rare cases, against the background of the use of combined oral contraceptives, development was observed, which in some cases led to life-threatening intra-abdominal bleeding. This should be taken into account when making a differential diagnosis in case of severe abdominal pain, liver enlargement, or signs of intra-abdominal bleeding.
. Other states
Women with hypertriglyceridemia while taking combined oral contraceptives (if there is a family history of this condition) may increase the risk of developing.
Although a slight increase in blood pressure has been described in many women taking combined oral contraceptives, a clinically significant increase has rarely been noted. However, if a persistent, clinically significant increase in blood pressure develops while taking combined oral contraceptives, these drugs should be discontinued and treatment initiated. Taking combined oral contraceptives can be continued if normal blood pressure values ​​are achieved with antihypertensive therapy.
The following conditions have been reported to develop or worsen both during pregnancy and when taking combined oral contraceptives, but their relationship with COC use has not been proven: jaundice and / or itching associated with cholestasis; the formation of stones in the gallbladder; ; ; hemolytic uremic syndrome; Sydenham; herpes of pregnant women; hearing loss associated with otosclerosis. Cases of Crohn's disease and non-specific ulcerative colitis have also been described with the use of combined oral contraceptives.
Occasionally, chloasma may develop, especially in women with a history of chloasma of pregnancy. Women with a tendency to chloasma while taking COCs should avoid prolonged exposure to the sun and exposure to ultraviolet radiation.
Acute or chronic liver dysfunction may require the withdrawal of COCs until liver function tests return to normal. Recurrence of cholestatic jaundice, which developed for the first time during pregnancy or previous use of sex hormones, requires discontinuation of COCs.
Although combined oral contraceptives may affect insulin resistance and glucose tolerance, there is no need to change the therapeutic regimen in diabetic patients using low-dose COCs (<0,05 мг этинилэстрадиола). Тем не менее, женщины с сахарным диабетом во время приема КОК должны тщательно наблюдаться.
If a woman with hirsutism has recent or severe symptoms, a differential diagnosis should be made to identify a possible cause (androgen-producing tumor, adrenal enzyme deficiency).

Laboratory tests
Taking combined oral contraceptives may affect the results of some laboratory tests, including liver, kidney, thyroid, adrenal function, plasma transport proteins, carbohydrate metabolism, coagulation and fibrinolysis parameters. Changes usually do not go beyond the boundaries of normal values.

Effect on the menstrual cycle
While taking combined oral contraceptives, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. Therefore, evaluation of any irregular bleeding should be done only after an adaptation period of approximately three cycles.
If irregular bleeding recurs or develops after previous regular cycles, a thorough examination should be carried out to exclude malignant neoplasms or pregnancy.
Some women may not develop withdrawal bleeding during the pill break. If combined oral contraceptives were taken as directed, it is unlikely that the woman is pregnant. However, if previously combined oral contraceptives were taken irregularly or if there are no consecutive withdrawal bleedings, pregnancy should be excluded before continuing to take the drug.

Medical examinations
Before starting the use of Diane-35, a woman is recommended to undergo a thorough general medical and gynecological examination (including examination of the mammary glands and a cytological examination of cervical mucus), to exclude pregnancy. In addition, violations of the blood coagulation system should be excluded.
In the case of long-term use of the drug, it is necessary to conduct regular check-ups (approximately every 6 months).
A woman should be warned that drugs such as Diane-35 do not protect against (AIDS) and other sexually transmitted diseases!

Influence on the ability to drive a car and machinery.
Not found.

Side effects that have been reported with the use of COCs, but the relationship of which with the use of the drug has not been confirmed or refuted.

Organ system Common (>1/100) Uncommon (>1/1000 and<1/100) Редко (<1/1000)
Organ of vision intolerance
contact lenses
Gastrointestinal nausea, vomiting pain,
tract in the abdomen
Immune System Reaction
hypersensitivity
General symptoms weight gain weight loss
Metabolism fluid retention
Nervous system headache migraine
Psychiatric decrease in mood, decrease in libido, increase in libido
mood swing disorders
Reproductive system Pain in the mammary glands, hypertrophy of the mammary glands Vaginal discharge
and mammary glands engorgement of the mammary glands discharge from the mammary glands
Skin and
subcutaneous tissue rash,
erythema multiforme

The following serious adverse events have been reported in women using combined oral contraceptives. These adverse events are discussed in the "Special Instructions" section:
. Venous thromboembolic disorders
. Arterial thromboembolic disorders
. Stroke
. hypertension
. Hypertriglyceridemia
. Changes in glucose tolerance or effects on peripheral insulin resistance
. Liver tumors (benign and malignant)
. Violation of the functional parameters of the liver
. Chloasma
. In women with hereditary angioedema, exogenous estrogens may cause or exacerbate the symptoms of angioedema.
. The onset or worsening of conditions for which the relationship with the use of combined oral contraceptives is not undeniable: jaundice and / or itching associated with cholestasis; the formation of gallbladder stones; porphyria; systemic lupus erythematosus; ; chorea; herpes of pregnant women; hearing loss associated with otosclerosis; Crohn's disease; ulcerative colitis; cervical cancer.
The frequency of diagnosing breast cancer in women using oral contraceptives is increased very slightly. Breast cancer is rarely observed in women under 40 years of age, the excess frequency is insignificant in relation to the overall risk of breast cancer. A causal relationship between the occurrence of breast cancer and the use of COCs has not been established. For more information, see the section "Contraindications" and "Special Instructions".

Interactions of oral contraceptives with other medicinal products may result in breakthrough bleeding and/or reduced contraceptive efficacy. Women taking these drugs should temporarily use barrier methods in addition to Diane-35, or choose another method of contraception. The following types of interaction have been reported in the literature.
Influence on hepatic metabolism: the use of drugs that induce microsomal liver enzymes may lead to an increase in the clearance of sex hormones. These drugs include: phenytoin, barbiturates, primidone, carbamazepine, rifampicin; there are also suggestions for oxcarbazepine, topiramate, felbamate, griseofulvin and preparations containing St. John's wort. HIV protease inhibitors (eg ritonavir) and non-nucleoside reverse transcriptase inhibitors (eg nevirapine) and combinations thereof also have the potential to interfere with hepatic metabolism.
Effects on enterohepatic circulation: According to separate studies, some antibiotics (eg penicillins and tetracyclines) can reduce the enterohepatic circulation of estrogens, thereby lowering the concentration of ethinylestradiol.
While taking drugs that affect microsomal enzymes, and within 28 days after their withdrawal, you should additionally use a barrier method of contraception.
While taking antibiotics (excluding rifampicin and griseofulvin) and within 7 days after their withdrawal, you should additionally use a barrier method of contraception. If the period of using the barrier method of protection ends later than the pills in the package, you need to move on to the next package of Diane-35 without the usual break in taking the pills. Oral combined contraceptives may interfere with the metabolism of other drugs, leading to an increase (eg, cyclosporine) or a decrease (eg, lamotrigine) in plasma and tissue concentrations.

Other forms of interaction
The use of drugs such as Diane-35 may affect the results of some laboratory tests, including liver biochemical parameters, plasma protein concentrations (for example, corticosteroid-binding globulin, lipid / lipoprotein fractions, hemostasis and fibrinolysis parameters, carbohydrate metabolism). These changes, as a rule, remain within normal physiological values.

Diane-35 should not be used in the presence of any of the conditions listed below. If any of these conditions develop for the first time while taking the drug, the drug should be immediately discontinued.
. Thrombosis (venous and arterial) and thromboembolism at present or in history (including deep vein thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular disorders).
. Conditions preceding thrombosis (including transient ischemic attacks,) at present or in history.
. Migraine with a history of focal neurological symptoms.
. Diabetes mellitus with vascular complications.
. Multiple or pronounced risk factors for venous or, including damage to the valvular apparatus of the heart, cardiac arrhythmias, diseases of the cerebral vessels or coronary arteries of the heart; uncontrolled arterial hypertension.
. Pancreatitis with severe hypertriglyceridemia at present or in
anamnesis.
. Severe (until liver function tests return to normal).
. Liver tumors (benign or malignant) at present or in history.
. Identified hormone-dependent malignant diseases (including genital organs or mammary glands) or suspicion of them.
. Vaginal bleeding of unknown origin.
. Pregnancy or suspicion of it.
. breastfeeding period.
. Hypersensitivity to any of the components of the drug Diane-35.
. Carefully
If any of the conditions / risk factors listed below are currently present, then the potential risk and expected benefit of using combined oral contraceptives should be carefully weighed in each individual case:
. Risk factors for the development of thrombosis and thromboembolism: smoking; thrombosis, myocardial infarction or cerebrovascular accident at a young age in any of the immediate relatives; ; dyslipoproteinemia (eg, hypertension; migraine; valvular heart disease; cardiac arrhythmias, prolonged immobilization, major surgery, major trauma)
. Other diseases in which peripheral circulatory disorders may occur:; systemic lupus erythematosus; hemolytic uremic syndrome; Crohn's disease and ulcerative colitis; sickle cell anemia; as well as superficial veins
. Hypertriglyceridemia
. Liver disease
. Diseases that first arose or worsened during pregnancy or due to a previous use of sex hormones (for example, jaundice, gallbladder disease, hearing loss, porphyria, herpes pregnant, Sydenham's chorea)

Pregnancy and lactation
Diane-35 is not prescribed during pregnancy and lactation.
If pregnancy is detected while taking Diane-35, the drug should be discontinued immediately. Cyproterone acetate is excreted in milk, so the use of Diane-35 is contraindicated during lactation.

Serious violations in case of overdose have not been reported. Symptoms that may occur in overdose include nausea, vomiting, spotting or metrorrhagia.
There is no specific antidote, symptomatic treatment should be carried out.

Diane-35 is a combined monophasic contraceptive with antiandrogenic properties.

Release form and composition

Dosage form - dragee (21 pieces in blisters, in a cardboard box 1 blister).

• Cyproterone acetate - 2 mg;
• Ethinylestradiol - 0.035 mg.

Excipients: corn starch, lactose monohydrate, povidone, magnesium stearate, talc (hydrogen silicate).

Shell composition: povidone 700,000, sucrose, macrogol 6000, titanium dioxide, calcium carbonate, mountain glycol wax, glycerol, iron (II) oxide, talc (magnesium hydrosilicate).

Pharmacological properties

Pharmacodynamics

Diane-35 is a low-dose monophasic oral estrogen-antiandrogen combination contraceptive. It prevents conception by inhibiting ovulation and changing the characteristics of the cervical secretion, which makes it impermeable to spermatozoa.

In women taking Diane-35, the menstrual cycle normalizes, the pain of menstruation and the intensity of bleeding decrease, which minimizes the risk of developing iron deficiency anemia. There are suggestions that the use of the drug is justified in order to prevent ovarian cancer and endometrial cancer.

Against the background of taking a contraceptive, the activity of the sebaceous glands decreases, which plays an important role in the occurrence of seborrhea and acne. A course of therapy lasting 3-4 months leads to the almost complete disappearance of acne and excessive oiliness of the skin of the scalp. It also slows down hair loss, which is often a symptom of seborrhea. Taking Diane-35 by women of reproductive age reduces the clinical manifestations of mild hirsutism (for example, increased facial hair growth), but the result of treatment becomes noticeable only after a few months of therapy.

Cyproterone acetate, in addition to being antiandrogenic, is also characterized by a pronounced progestogenic effect.

Pharmacokinetics of cyproterone acetate

When taken orally, cyproterone acetate is completely absorbed almost regardless of dose. After oral administration of Diane-35, the maximum serum level of the compound of 15 ng / ml is reached after 1.6 hours. The absolute bioavailability of cyproterone acetate is approximately 88% of the dose.

This active component of the contraceptive binds only to serum albumin. Approximately 3.5-4% of cyproterone acetate remains in the free form in the blood serum. The increase in SHBG caused by ethinyl estradiol does not affect the binding of the compound to serum proteins. The average apparent volume of distribution is 986 ± 437 liters.

Cyproterone acetate is metabolized by conjugation or hydroxylation. The main metabolite in human plasma is the 15β-hydroxyl derivative.

A certain part of the dose of Diane-35 is excreted unchanged in the bile. Most of the cyproterone acetate contained in it is excreted as metabolites in the urine or bile in a ratio of 1:2. The elimination half-life of eliminated metabolites from plasma is 1.8 days.

Since there is no specific protein binding, a change in the concentration of sex steroid-binding globulin (SHBG) does not affect the pharmacokinetics of cyproterone acetate. During the menstrual cycle, the highest equilibrium concentration of this substance in the blood serum is observed in the second half of the cycle.

Pharmacokinetics of ethinylestradiol

After oral administration, ethinylestradiol is completely absorbed in a minimum period of time. Its maximum concentration in blood serum, which is 71 pg / ml, is reached in 1.6 hours. In the process of absorption and "first passage" through the liver, ethinylestradiol forms metabolites, and its bioavailability averages about 45%.

The compound almost completely (98%) binds to albumin, but not in a specific way. It contributes to the synthesis of SHPS. The apparent volume of distribution of ethinylestradiol is 2.8–8.6 l/kg.

Ethinylestradiol is subject to presystemic conjugation in the liver and in the mucosa of the small intestine. The main route of its metabolism is aromatic hydroxylation. The rate of clearance from plasma is 2.3–7 ml/min/kg.

The equilibrium concentration of ethinylestradiol is reached during the second half of the course of treatment.

Indications for use

The use of the drug is indicated for women with androgenization phenomena as oral contraception.

In addition, Diane-35 is prescribed for the treatment of androgen-dependent diseases in women: severe forms of acne, accompanied by seborrhea, the formation of inflammatory nodes, including nodular cystic acne, papular-pustular acne; mild forms of hirsutism; androgenetic alopecia.

Contraindications

• Thromboembolism and thrombosis, including history (cerebrovascular disorders, deep vein thrombosis, myocardial infarction, pulmonary embolism);
• Presence of multiple or severe signs of risk of arterial or venous thrombosis;
• Angina pectoris, transient ischemic attacks and other conditions preceding thrombosis;
• Tumors of the liver, including a history;
• Liver disease or severe functional impairment;
• Pancreatitis, including a history, if it was accompanied by severe hypertriglyceridemia;
• Diabetes mellitus complicated by microangiopathies;
• A history of migraine that proceeded with focal neurological symptoms;
• Uterine bleeding of unknown origin;
• Hormone-dependent malignant neoplasms, including tumors of the genital organs or breast (including history);
• Hypersensitivity to the components of the drug.

The drug must be immediately discontinued if any of these pathologies develops for the first time during the use of Diane-35.

The drug is also contraindicated in cases of suspected pregnancy, during gestation and breastfeeding.

Instructions for use Diane-35: method and dosage

Dragee is taken orally, without chewing, with a small amount of liquid, preferably immediately after breakfast or dinner.

Dosing of the drug - 1 tablet per day.

Reception begins on the first day of the cycle, using from the calendar package of dragees of the corresponding day of the week, at a time convenient for the patient, with the condition that subsequent doses will necessarily be carried out at this particular hour of the day.

For each subsequent reception, dragees are used from the cell, which is indicated by the arrow applied to the foil from the previous one. Following the direction on the calendar package, the woman takes all 21 pills and takes a break of 7 days, during which bleeding similar to menstruation passes. One course of therapy lasts 28 days, of which 21 days are pills and 7 days are a break. It must be remembered that the reception should not be interrupted for more than 7 days and the first 7 days of taking the dragee are required to achieve an appropriate suppression of the function of the hypothalamic-pituitary-ovarian system.

The day of taking the drug from the next package should coincide with the day of the week on the calendar package of the previous course and begin on the 8th day after the start of the break at a strictly set time.

To switch from combined oral contraceptives to the use of Diane-35, it is necessary to start taking the next day after the last pill from the package with the active substances of the previous remedy, for a calendar pack of 28 pills and no later than 1 day after a 7-day break, for contraceptives from 21 dragee.

To switch from preparations consisting only of gestagens (“mini-pills”), Diane-35 can be taken without interruption, with injectable forms of contraception - from the day of the next injection, from the implant - on the day of its removal. With each of these transitions, it is additionally necessary to use a barrier method of contraception during the first 7 days.

When performing an abortion in the 1st trimester of pregnancy, oral contraception is started immediately, in which case additional methods of contraception are not required.

In the absence of sexual intercourse after an abortion in the second trimester of pregnancy or childbirth, it is recommended to start using the drug on the 21-28th day. If a woman started taking later, then during the first 7 days, a barrier method of contraception should be used in parallel. Patients who lived sexually between abortion or childbirth and the start of the drug should wait until the first menstruation or exclude the presence of pregnancy.

If a woman misses taking a pill at the set time, it should be taken as soon as possible, and the next pill at the usual time. The reliability of contraception is not impaired if the delay is less than 12 hours.

In the case when more than 36 hours have passed since the last dose (more than 12 hours late), the missed pill should be taken as soon as remembered, even if it will be taking two pills at the same time, while the next dose is taken at the usual time. If the violation occurred in the first or second week of use, it is necessary to use a barrier method of contraception for the next 7 days. In case of a delay of more than 12 hours during the third week of admission, at the end of the calendar package, there is no need to take a break in the reception, it is necessary to continue taking it from the next blister. While taking from the second package, a woman may experience bloody spotting or breakthrough uterine bleeding.

If the patient vomited after taking the dragee (in the first 3-4 hours), the absorption of the active substances may be impaired and incomplete, so you should use the recommendations for the case of missing a dose.

To delay the onset of menstruation, it is necessary to continue taking the pills from the new calendar package without taking a 7-day break. You can take dragees from the second package until it ends. You should be aware that during this period, the patient may experience spotting or breakthrough bleeding. After a 7-day break, you should continue using Diane-35 from a new package.

To change the day of the beginning of the menstrual cycle to another, the next break should be reduced by the required number of days. The fewer days of the break, the greater the likelihood of the absence of withdrawal bleeding and the presence of spotting spotting during the period of taking the dragee.

The duration of the drug in the treatment of hyperandrogenic pathologies depends on the severity of the condition, after the disappearance of the signs of the disease, it is recommended to continue taking the dragee for 3-4 months. If a relapse occurs, you can repeat the course of therapy.

Side effects

The use of the drug can cause side effects:

• From the reproductive system: rarely - intermenstrual bleeding, changes in libido, violations of the vaginal secretion;
• From the digestive system: rarely - nausea and vomiting;
• From the nervous system: rarely - migraine, decreased mood, headache;
• From the endocrine system: rarely - a change in body weight, engorgement, enlargement, soreness of the mammary glands and discharge from them;
• Other: very rarely - allergic reactions, poor tolerance to contact lenses, the appearance of age spots on the face (chloasma).

These side effects may appear in the first months of taking the drug and, as a rule, gradually decrease.

Overdose

Symptoms of an overdose of Diane-35 are slight bleeding from the vagina (in girls), nausea, and vomiting. There is no specific antidote. If necessary, symptomatic therapy is prescribed.

special instructions

The use of Diane-35 can only be started after a general medical examination, including a cytological examination of cervical mucus, mammary glands, to exclude violations of the blood coagulation system and the presence of pregnancy. Control examinations with long-term use of the drug are recommended to be carried out once every six months.

In the presence of risk factors, a woman should make a decision about the upcoming therapy, carefully assessing the potential risk and expected benefit from taking the drug.

A woman should be informed about the possible development of arterial or venous thrombosis, and about the need for immediate medical attention in the event of the first symptoms. They include: movement disorders; swelling and/or unilateral leg pain; sharp pain in the chest with irradiation to the left arm or without irradiation; unexpected shortness of breath and/or coughing fit; severe and prolonged headache; increased severity and frequency of migraine; sudden loss of vision (partial or complete); diplopia; dizziness; slurred speech or aphasia; other.

With the appearance of persistent arterial hypertension, the drug should be discontinued, after appropriate antihypertensive therapy and normalization of blood pressure, the contraceptive may be continued.

The occurrence of functional disorders of the liver may require a temporary withdrawal of Diane-35 until the normalization of laboratory parameters. With recurrent cholestatic jaundice, you should stop taking combined oral contraceptives.

Patients with diabetes mellitus do not need to adjust the dose of hypoglycemic drugs, but women in this category should be under special medical supervision.

Evaluation of irregular bleeding (spotting or breakthrough bleeding) that occurs during the use of Diane-35 in the first months of therapy should be carried out after an adaptation period that lasts three cycles.

The development of irregular bleeding after previous systematic cycles should involve consideration of non-hormonal causes, diagnostic measures to exclude pregnancy or malignant neoplasms, including curettage.

When conducting a differential diagnosis in women with hirsutism, the causes of the appearance or significant increase in the symptoms of the disease should include an androgen-producing tumor, congenital dysfunction of the adrenal cortex.

In the absence of withdrawal bleeding during the 7-day break after taking two calendar packs of the drug in a row, it is recommended to exclude pregnancy before continuing.

Influence on the ability to drive vehicles and complex mechanisms

According to available data, Diane-35 does not significantly affect the ability to drive vehicles or mechanisms with a complex operating principle.

Application in childhood

According to the instructions, Diana-35 is prescribed to adolescents only after the onset of menarche.

For impaired liver function

If liver dysfunction occurs, it is advisable to temporarily discontinue the drug until laboratory parameters improve. Recurrent cholestatic jaundice, first diagnosed during pregnancy or a previous course of sex hormone therapy, is an indication for discontinuation of Diane-35.

drug interaction

The contraceptive reliability of Diane-35 is reduced when taken simultaneously with tetracyclines and ampicillins.

When combined with inducers of microsomal hepatic enzymes, including barbiturates, hydantoins, primidone, rifampicin, carbamazepine, and possibly with topiramate, oxcarbazepine, felbamate and griseofulvin, an increase in the clearance of active substances occurs, this can cause breakthrough uterine bleeding and reduce the reliability of contraception.

Analogues

Analogues of Diana-35 are: Belluna-35, Erica-35, Chloe.

Terms and conditions of storage

Store at room temperature. Keep away from children.

Shelf life - 5 years.