Diane-35 dragee №21

Packing

Mechanism of action

Pharmacodynamics

Diane-35 is a low-dose monophasic oral combination estrogen-antiandrogenic contraceptive drug.

The contraceptive effect of Diane-35 is accomplished through complementary mechanisms, the most important of which are the suppression of ovulation and changes in the properties of the cervical secretion, as a result of which it becomes impermeable to spermatozoa.

In women taking combined oral contraceptives, the menstrual cycle becomes more regular, painful menstruation is less common, the intensity of bleeding decreases, resulting in a reduced risk of iron deficiency anemia. In addition, there is evidence that the risk of endometrial cancer and ovarian cancer is reduced.

Against the background of Diane-35, the increased activity of the sebaceous glands decreases, 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 oily hair and skin disappears even earlier. Hair loss that often accompanies seborrhea is also reduced. Diane-35 therapy in women of reproductive age reduces the clinical manifestations of mild forms of hirsutism (in particular, increased facial hair growth); however, the effect of treatment should be expected only after several months of use. Along with the above described antiandrogenic effect, cyproterone acetate also has a pronounced progestogenic effect.

Pharmacokinetics

Cyproterone Acetate

Absorption. When ingested cyproterone acetate is completely absorbed in a wide range of doses. After ingestion of Diane-35 dragee, the maximum concentration (C max) 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 free form is only about 3.5-4% of the total serum concentration. An ethinylestradiol-induced increase in SHBG 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 a 15P-hydroxyl derivative.

Inference. Some of the dose is excreted unchanged with the bile. Most of the dose is excreted in the form of metabolites in urine or bile in a 1: 2 ratio. Plasma metabolites are eliminated with a half-life of 1.8 days.

Equilibrium concentration. Since protein binding is not specific, changes in the level of the globulin that binds sex steroids (GSPS) do not affect the pharmacokinetics of cyproterone acetate. During the cycle treatment, the maximum equilibrium serum concentration of cyproterone acetate is achieved in the second half of the cycle.

Ethinyl Estradiol

Absorption. After ingestion, ethinyl estradiol is rapidly and completely absorbed. The maximum concentration (C max) in serum, equal to about 71 pg / ml, is reached in 1.6 hours. During absorption and first passage through the liver, ethinyl estradiol is metabolized, with the result that its bioavailability on ingestion is on average about 45%.

Distribution. Ethinyl estradiol is almost completely (approximately 98%), although not specific, bound by albumin. Ethinyl estradiol induces synthesis of SHBG. The apparent volume of distribution of ethinyl estradiol is 2.8– 8.6 l / kg.

Metabolism. Ethinyl estradiol is subjected to presystemic conjugation, both in the mucous membrane of the small intestine 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.

Inference. The decrease in the concentration of ethinyl estradiol in the serum is biphasic; The first phase is characterized by a half-life of about 1 hour, the second is 10-20 hours. Unchanged from the body is not displayed. Ethinyl estradiol metabolites are excreted in urine and bile in a ratio of 4: 6 with a half-life of about 24 hours.

Equilibrium concentration. Equilibrium concentration is reached during the second half of the treatment cycle.

Indications and usage

Contraception in women with androgenization.

Treatment of androgen-dependent diseases in women, such as acne, especially common forms and forms, accompanied by seborrhea, inflammation or the formation of nodules (papular-pustular acne, nodular cystic acne); androgenetic alopecia and mild forms of hirsutism.

Contraindications

Diane-35 should not be applied in the presence of any of the conditions listed below.If any of these conditions develop for the first time while receiving, the drug should be immediately canceled.

• Thrombosis (venous and arterial) and thromboembolism currently or in history (including deep vein thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular disorders).
• The states preceding thrombosis (including transient ischemic attacks, angina pectoris) are currently or in history.
• Migraine with focal neurological symptoms in history
• Diabetes with vascular complications.
• Multiple or severe risk factors for venous or arterial thrombosis, including valvular heart disease, cardiac arrhythmias, vascular diseases of the brain or coronary arteries; uncontrolled arterial hypertension.
• Pancreatitis with severe hypertriglyceridemia now or in history.
• Severe liver disease (until liver function indexes return to normal).
• Liver tumors (benign or malignant) currently or in history.
• Identified hormone-dependent malignant diseases (including genitals or mammary glands) or suspicion of them.
• Vaginal bleeding of unknown origin.
• Pregnancy or suspicion of her.
• Lactation period.
• Hypersensitivity to any of the components of the drug Diane-35

Carefully

If any of the conditions / risk factors listed below are present, then the potential risk and the expected benefits of using combined oral contraceptives should be carefully weighed in each individual case:

• Risk factors for thrombosis and thromboembolism: smoking; thrombosis, myocardial infarction or cerebral circulation at a young age in one of the closest relatives; obesity; dyslipoproteinemia (for example, arterial hypertension; migraine; valvular disease; cardiac arrhythmias, prolonged immobilization, serious surgical interventions, extensive trauma
• Other diseases in which violations of the peripheral circulation can occur: diabetes mellitus; systemic lupus erythematosus; hemolytic uremic syndrome; Crohn's disease and ulcerative colitis; sickle cell anemia; as well as phlebitis of superficial veins
• Hypertriglyceridemia
• Liver diseases
• Diseases that first arose or aggravated during pregnancy or against the background of previous intake of sex hormones (for example, jaundice, cholestasis, gallbladder disease, otosclerosis with impaired hearing

Pregnancy and Breastfeeding

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

Special notes

If any of the conditions / risk factors listed below are present, then the potential risk and the expected benefits of Diane-35 treatment in each individual case should be carefully weighed and discussed with the woman before she decides to start taking the drug. In the event of a worsening, aggravation, or first manifestation of any of these conditions or risk factors, the woman should consult with her physician, who may decide 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 deep vein thrombosis, pulmonary thromboembolism, myocardial infarction, stroke) with combined oral contraceptives.

The risk of venous thromboembolism (VTE) is maximum in the first year of taking such drugs. The approximate incidence of VTE among women taking low-dose oral contraceptives (<0.05 mg ethinyl estradiol) is up to 4 per 10,000 people / years compared to 0.5-3 per 10,000 people / years among women who do not use the combined oral contraceptives. The incidence of VTE during pregnancy is 6 per 10,000 man / years.

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);

in the presence of:

• family history (ie, venous or arterial thromboembolism ever with close relatives or parents at a relatively young age); in the case of 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 more than 30 kg / m);
• dyslipoproteinemia;
• hypertension;
• migraine;
• valvular heart disease;
• atrial fibrillation;
• prolonged immobilization, serious surgery, any surgery on the legs or an extensive injury. In these situations, it is advisable to stop using the combined oral contraceptives (in the case of the planned operation, at least four weeks before it) and not to resume reception within two weeks after the end of immobilization.

The question of the possible role of varicose veins and superficial thrombophlebitis in the development of venous thromboembolism remains controversial. The increased risk of thromboembolism in the postpartum period should be considered. Peripheral circulation disorders can also occur in diabetes mellitus, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis), and sickle cell anemia. An increase in the frequency and severity of migraine during the use of combined oral contraceptives (which may precede cerebrovascular impairment) may be grounds for immediate discontinuation of these drugs. • Tumors There have been reports of some increase in the risk of cervical cancer with prolonged use of combined oral contraceptives. Relationship with the reception of combined oral contraceptives is not proven. There are contradictions regarding the extent to which these findings are associated with screening for cervical pathology or with the characteristics of sexual behavior (more rare use of barrier methods of contraception). The most significant risk factor for cervical cancer is persistent papilloma viral infection.

It has also been found that there is a slightly increased relative risk of developing breast cancer diagnosed in women who used combined oral contraceptives. The increased risk gradually disappears within 10 years after discontinuation of these drugs. His connection with the reception of combined oral contraceptives has not been proven. The observed increase in risk may also be due to an 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, on the background of the use of combined oral contraceptives, development of liver tumors was observed, which in some cases led to life-threatening intra-abdominal bleeding. In the event of severe abdominal pain, enlargement of the liver or signs of intra-abdominal bleeding, this should be considered when conducting a differential diagnosis.

Other states
In women with hypertriglyceridemia (in the presence of this condition in the family history), there may be an increased risk of developing pancreatitis while taking combined oral contraceptives.

Although a slight increase in blood pressure has been reported in many women taking combined oral contraceptives, clinically significant increases have been rare. However, if a persistent, clinically significant increase in blood pressure develops while taking combined oral contraceptives, these drugs should be canceled and treatment of hypertension should begin. Reception of combined oral contraceptives can be continued if normal blood pressure values ​​are achieved with the help of 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 taking combined oral contraceptives has not been proven: jaundice and / or itching associated with cholestasis; the formation of gallstones; porphyria; systemic lupus erythematosus; hemolytic uremic syndrome; chorea; herpes pregnant; hearing loss associated with otosclerosis. Also described are cases of Crohn's disease and ulcerative colitis associated with the use of combined oral contraceptives.

Chloasma can sometimes develop, especially in women with a history of pregnant chloasma. Women with a tendency to chloasma while taking combined oral contraceptives should avoid prolonged exposure to the sun and exposure to ultraviolet radiation.Acute or chronic abnormal liver function may require the abolition of combined oral contraceptives, until the liver function returns to normal. Relapse of cholestatic jaundice, which developed for the first time during pregnancy or a previous intake of sex hormones, requires discontinuation of combined oral contraceptives.

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 combined oral contraceptives (<0.05 mg of ethinyl estradiol). However, women with diabetes should be carefully monitored while taking combined oral contraceptives.

If a woman suffering from hirsutism has recently developed symptoms or is highly pronounced, a differential diagnosis should be made in order to identify the possible cause of the disease (androgen-producing tumor, deficiency of adrenal enzymes).

Laboratory tests
Acceptance of combined oral contraceptives can affect the results of some laboratory tests, including indicators of liver, kidney, thyroid, adrenal glands, plasma transport protein levels, carbohydrate metabolism, coagulation and fibrinolysis parameters. Changes usually do not go beyond the normal range.

Effect on the menstrual cycle
Irregular bleeding (spotting or breakthrough bleeding) may occur during combined oral contraceptives, especially during the first months of use. Therefore, any irregular bleeding should be evaluated only after a period of adaptation of approximately three cycles. If irregular bleeding recurs or develops after previous regular cycles, a thorough examination should be performed to rule out malignant tumors or pregnancy.

Some women may not develop withdrawal bleeding during a break in the dragee taking. 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 two withdrawal bleedings in a row, pregnancy should be excluded before continuing to take the drug.

Medical examinations
Before starting the use of the drug Diane-35, a woman is recommended to undergo a thorough general medical and gynecological examination (including the examination of the mammary glands and cytological examination of the cervical secret), to exclude pregnancy. In addition, violations of the blood coagulation system should be excluded.

In case of prolonged use of the drug, it is necessary to conduct control examinations every 6 months.

A woman should be warned that Diane-35 drugs do not protect against HIV infection (AIDS) and other sexually transmitted diseases!

Influence on the ability to drive and technology.
Not found.

1 tablet contains:
active substances: ethinyl estradiol 35 mcg and cyproterone acetate 2 mg;
Excipients: lactose monohydrate, corn starch, polyvidone 25 000, Magnesium stearate, sucrose, polyvidone 700 000, macrogol 6000, Calcium carbonate precipitated, talc, glycerol 85%, titanium dioxide, ferric oxide yellow, ferric oxide red, mounting glycolic wax

Diane-35 dragee should be taken orally in the order indicated on the package, every day at about the same time, with a small amount of water. Take one dragee per day continuously for 21 days. Receiving the next pack begins after a 7-day break in taking the dragee, during which withdrawal bleeding usually occurs. Bleeding, as a rule, begins 2-3 days after taking the last dragee and may not end before the start of taking a new package.

The duration of treatment depends on the severity of androgenization symptoms, as well as on their response to treatment. As a rule, treatment should be continued for several months. With acne and seborrhea, the answer usually comes earlier than with hirsutism or alopecia.

After alleviating the symptoms, it is recommended to take Diane-35 for at least 3-4 cycles. If within a few weeks or months after discontinuation of dragee ingestion a relapse occurs, treatment of Diane-35 can be resumed.If the signs of androgenization recur after cessation of treatment, the possibility of an earlier resumption of Diane-35 should be considered.

How to start taking Diane-35

• In the absence of taking any hormonal contraceptives in the previous month.
  Reception of Diane-35 begins on the first day of the menstrual cycle (ie, on the first day of the menstrual bleeding). It is allowed to start taking for 2-5 menstrual cycles, but in this case it is recommended to additionally use a barrier method of contraception during the first 7 days of taking pills from the first package.
• When switching from other combined oral contraceptives.
  It is preferable to start taking Diane-35 the next day after taking the last active dragee from the previous package, but in no case later than the next day after the usual 7-day break (for preparations containing 21 dragees).
  When switching from contraceptives containing only gestagens (“mini-pilli”, injection forms, implant) or from a progestogen-releasing intrauterine contraceptive.
  A woman can go from “mini-pili” to Diane-35 on any day (without a break), from an implant or an intrauterine contraceptive with a progestogen — on the day of its removal, from an injection form — from the day the next injection should have been given. In all cases, you must use an additional barrier method of contraception during the first 7 days of taking pills.
• After an abortion in the first trimester of pregnancy.
  A woman can start taking the drug immediately. Subject to this condition, the woman does not need additional contraceptive protection.
• After childbirth or abortion in the second trimester of pregnancy. It is recommended to start taking the drug on the 21-28 day after birth or abortion in the second trimester of pregnancy. If reception is started later, it is necessary to use an additional barrier method of contraception during the first 7 days of taking pills. However, if a woman has already lived sexually, before the start of Diane-35, pregnancy should be excluded or it is necessary to wait for the first menstruation.

Reception of the missed dragees

If the delay in taking the drug was less than 12 hours, contraceptive protection is not reduced. A woman should take dragee as soon as possible, the next is taken at the usual time.

If the delay in taking the dragee is more than 12 hours, contraceptive protection can be reduced. In this case, you can follow the following two basic rules:

The drug should never be interrupted for more than 7 days.

7 days of continuous taking pills are required to achieve adequate suppression of the hypothalamic-pituitary-ovarian regulation.

Accordingly, the following tips can be given if the delay in taking the pills was more than 12 hours (the interval since the reception of the last bean is more than 36 hours):

• First week of taking the drug

A woman should take the last missed dragee as soon as possible, as soon as she remembers (even if it means taking two dragees at the same time). The following pills are taken at the usual time. Additionally, a barrier method of contraception (for example, a condom) should be used within the next 7 days. If sexual intercourse took place within a week before skipping dragees, it is necessary to take into account the probability of pregnancy. The more drops are missed, and the closer they are to a break in taking active substances, the greater the likelihood of pregnancy.

• The second week of taking the drug

A woman should take the last missed dragee as soon as possible, as soon as she remembers (even if it means taking two dragees at the same time). The following pills are taken at the usual time.

Provided that the woman took the pills correctly for 7 days preceding the first missed pills, there is no need to use additional contraceptive measures. Otherwise, as well as skipping two or more dragees, it is necessary to additionally use barrier methods of contraception (for example, a condom) for 7 days.

• The third week of taking the drug

The risk of reducing the reliability is inevitable due to the upcoming break in taking pills.

A woman should strictly adhere to one of the following two options. Moreover, if in the 7 days preceding the first missed pills, all the pills were taken correctly, there is no need to use additional contraceptive methods.

1. A woman should take the last missed dragee as soon as possible, as soon as she remembers (even if it means taking two dragees at the same time). The next dragee is taken at the usual time until the dragee from the current package is finished. The next package should start immediately. Withdrawal bleeding is unlikely until the second package ends, but there may be spotting and breakthrough bleeding while taking pills.
2. A woman can also interrupt the taking of pills from the current package. Then she should take a break for 7 days, including the day of skipping pills, and then start taking a new package.

If a woman misses pills, and then during a break in taking pills, she has no withdrawal bleeding, it is necessary to exclude pregnancy.

Recommendations in case of vomiting and diarrhea
If a woman has vomiting or diarrhea within 4 hours after taking active dragees, absorption may not be complete and additional contraceptive measures should be taken. In these cases, you should focus on the recommendations when skipping dragees.

Change the day of the beginning of the menstrual cycle
In order to delay the onset of menstruation, a woman must continue to take pills from the new Diane-35 package immediately after all pills from the previous one are taken, without interruption in reception. Drops from this new package can be taken as long as the woman wants (until the package ends). While taking the drug from the second package, a woman may have spotting or breakthrough uterine bleeding. Resume taking Diane-35 from a new pack should be after the usual 7-day break.

In order to postpone the onset of menstruation to another day of the week, a woman should be advised to shorten the nearest break in taking pills for as many days as she wants. The shorter the interval, the higher the risk that she will not have withdrawal bleeding, and further there will be spotting and breakthrough bleeding while taking the second package (as well as when she would like to delay the onset of menstruation.

On the part of the endocrine system: in rare cases - engorgement, tenderness, an increase in the mammary glands and discharge from them, a change in body weight.
From the reproductive system: in rare cases - intermenstrual bleeding, changes in vaginal secretions, changes in libido.
From the side of the central nervous system: in rare cases - headache, migraine, decrease in mood.
From the digestive system: in rare cases - nausea, vomiting.
Other: in very rare cases - poor tolerance of contact lenses, allergic reactions, the appearance of age spots on the face (chloasma).

These side effects may develop in the first few months of taking Diane-35 and usually decrease with time.

The interaction of oral contraceptives with other drugs can lead to breakthrough bleeding and / or a decrease in contraceptive reliability. The following types of interactions have been reported in the literature.

Effects on hepatic metabolism: the use of drugs that induce liver microsomal enzymes can lead to an increase in the clearance of sex hormones. Such drugs include: phenytoin, barbiturates, primidone, Carbamazepine, rifampicin; there are also suggestions for oxcarbazepine, topiramate, felbamate, ritonavir and Griseofulvin and preparations containing St. John's wort.

Effects on the enterohepatic circulation: according to individual studies, some antibiotics (for example penicillins and tetracycline) can reduce the enterohepatic circulation of estrogen, thereby lowering the concentration of ethinyl estradiol.

During the taking of drugs that affect microsomal enzymes, and within 28 days after they are canceled, you should additionally use a barrier method of contraception.

Overdose

No serious violations in overdose were reported. Symptoms that may occur with an overdose: nausea, vomiting, spotting or metrorrhagia. There is no specific antidote; symptomatic treatment should be carried out.

At a temperature not higher than 30 ° C. Keep out of the reach of children.