Cyproterone, Ethinyl Estradiol

Pharmacological properties

Both active ingredients that make up the Diane-35 preparation have a positive effect on the state of hyperandrogenism. Cyproterone acetate is a competitive antagonist of androgen receptors, it inhibits the synthesis of androgens and determines the decrease in the concentration of these hormones in the blood due to the antigonadotropic effect. this antigonadotropic effect is enhanced by ethinyl estradiol, which also regulates the synthesis of globulin, which binds sex steroids (HHCS) in blood plasma. with this in mind, the level of unbound bioavailable androgen in the blood decreases.

When using the drug Diane-35 (usually after 4 months of therapy), acne is eliminated, excessive oily hair and skin disappear even earlier. The hair loss that often accompanies seborrhea is also reduced. When using the drug by people with mild forms of hirsutism (primarily with mild facial hair growth), the results of therapy should be expected only after a few months from its start.

The contraceptive effect of Diane-35 is based on the interaction of various factors, the most important of which are suppression of ovulation and a change in cervical secretion. In addition to preventing pregnancy, the drug has a number of positive properties. The menstrual cycle becomes more regular, menstruation is less painful, and blood loss is reduced. The latter helps to reduce the incidence of iron deficiency anemia.

The toxicity profile of ethinyl estradiol is well understood. There are no preclinical data supplementing the information regarding the safety of ethinyl estradiol indicated in the sections of the instructions for medical use of the drug.

Data from standard preclinical toxicity studies with repeated use of cyproterone acetate do not indicate the existence of any specific risk to the human body.

Available clinical experience does not suggest that the incidence of liver tumors in humans is increased. The carcinogenicity studies of cyproterone acetate carried out in rodents do not indicate the existence of any specific carcinogenic effect. However, it should be borne in mind that sex steroids can contribute to the growth of certain hormone-dependent tumors that exist before.

Available data do not give reason to object to the use of the drug Diane-35 in people when taking it in accordance with the guidelines and in the recommended dose.

Cyproterone acetate

After oral administration of cyproterone, acetate is rapidly and completely absorbed. Its peak concentration in blood serum is 15 ng / ml and is achieved approximately 1.6 hours after a single application. The bioavailability of cyproterone acetate is approximately 88%.

Cyproterone acetate is almost completely bound to serum albumin. Only 3.5–4% of the total steroid concentration remains unbound. The increase in SHG levels induced by ethinyl estradiol does not affect protein binding of cyproterone acetate.

Cyproterone acetate is almost completely metabolized. The main metabolite in blood plasma is 15c-OH-CPA. Serum clearance rate is approximately 3.6 ml / min / kg.

The concentration of cyproterone acetate in the blood serum decreases two-phase with a half-life of 0.8 hours and 2.3-3.3 days. Some of the steroid is excreted unchanged. Metabolites are excreted in urine and bile in a ratio of 1: 2. The half-life of metabolites is 1.8 days.

Given the long half-life of cyproterone acetate from blood serum, its cumulation in blood serum can be observed during one cycle of therapy with a coefficient of 2–2.5.

Ethinyl estradiol

Adsorption

When taken orally, ethinyl estradiol is rapidly and completely absorbed.A peak serum concentration of approximately 71 pg / ml is reached after 1.6 hours.

Distribution

Ethinyl estradiol is strong, however, non-specifically binds to serum albumin (approximately 98%) and induces an increase in the concentration of GPS in serum.

Ethinyl estradiol is metabolized mainly by aromatic hydroxylation, and a large number of hydroxylated and methylated metabolites are formed, among which there are both free metabolites and conjugates with glucuronides and sulfates. The clearance is 2.3–7 ml / min / kg.

The level of ethinyl estradiol in blood serum decreases in 2 phases with a half-life of approximately 1 and 10–20 hours, respectively. The substance is not excreted unchanged, ethinyl estradiol metabolites are excreted in the urine and bile in a ratio of 4: 6. The half-life of metabolites is approximately 1 day.

Equilibrium concentration is achieved in the second half of the intake cycle, when the level of active substance in the blood serum is 60% higher compared to a single dose.

Indications

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

Application

Diane-35 is intended for regular use in order to achieve a therapeutic effect and the necessary contraceptive protection. the use of other hormonal contraceptives should be discontinued. the method of application of the drug Diane-35 does not differ from the usual regimen of administration of the majority of combined oral contraceptives (PDA). With this in mind, you should adhere to the same instructions regarding the method of use of the drug. irregular intake of Diane-35 can cause intermenstrual bleeding and worsen therapeutic and contraceptive effectiveness.

If hormonal contraceptives in the previous period (last month) were not used

Dragee administration should begin on the 1st day of the menstrual cycle. You can start taking it from day 2-5, however, in this case, during the first cycle, it is recommended to additionally use the barrier method of contraception during the first 7 days of taking the drug.

Switching from another PDA

It is advisable to start taking Diane-35 the day after taking the last active tablet of the previous PDA, at least no later than the next day after the break in taking the tablets or after taking the placebo tablets of her previous PDA.

Transition from a method based on the use of only a progestogen (mini-pill, injection, implant) or an intrauterine system with a progestogen

You can start taking Diane-35 any day after stopping the mini-pill (with an implant or intrauterine system - on the day of their removal; in case of injection, instead of the next injection). However, in all cases, it is recommended to additionally use the barrier method of contraception during the first 7 days of taking the dragee.

After an abortion in the first trimester of pregnancy

You can start using Diane-35 immediately. In this case, there is no need to use additional contraceptives.

After childbirth or abortion in the second trimester of pregnancy

In case of breastfeeding, see the subsection "Pregnancy and lactation period".

It is recommended that you start taking Diane-35 from the 21st to 28th day after childbirth or abortion in the second trimester of pregnancy. At a later start of dragee administration, an additional barrier method of contraception should be used during the first 7 days of taking the drug. However, if sexual intercourse has already taken place, then before starting the use of CPC, it is necessary to exclude pregnancy or wait for menstruation.

What to do if you skip a dragee

If the delay in taking dragees does not exceed 12 hours, the contraceptive effect of the drug does not decrease. Missed dragees must be taken as soon as possible. The next dragee from this package is taken at the usual time.

If the delay in taking the missed dragee exceeds 12 hours, contraceptive protection may be reduced. In this case, you can be guided by two basic rules:

a break in taking dragees can never exceed 7 days;

adequate inhibition of the hypothalamus - pituitary - ovary system is achieved by continuous use of dragees for 7 days.

Accordingly, in everyday life should be guided by the following recommendations:

1st week

You should take the last missed dragee as soon as possible, even if you have to take 2 dragees at a time. After that, they continue to take dragees at the usual time. In addition, over the next 7 days it is necessary to use a barrier method of contraception, such as a condom. If sexual intercourse took place in the previous 7 days, you need to consider the likelihood of pregnancy. The more dragees missed and the closer the break in taking the drug, the higher the likelihood of pregnancy.

2nd week

You should take the last missed dragee as soon as possible, even if you have to take 2 dragees at a time. After that, they continue to take dragees at the usual time. Provided that the pills are taken correctly for 7 days before the first pass, there is no need to use additional contraceptives. In another case, or when skipping more than 1 tablet, it is recommended to additionally use the barrier method of contraception for 7 days.

3rd week

The risk of a decrease in reliability increases with the approach of a break in taking dragees. However, by observing the dragee administration regimen, contraceptive protection reduction can be avoided. If you adhere to one of the following options, then there will be no need to use additional contraceptives, provided that the pill is taken correctly for 7 days before skipping. If this is not the case, you must adhere to the first of the following options and use additional methods of contraception for the next 7 days.

You should take the last missed dragee as soon as possible, even if you have to take 2 dragees at a time. After that, they continue to take dragees at the usual time. Dragees from the next package should be taken immediately after the previous one, that is, there should be no breaks between packages. It is unlikely that menstrual bleeding will begin by the end of taking the second package, although bleeding or breakthrough bleeding is possible while taking the dragee.

You can also advise to stop taking dragees from the current package. In this case, the break in taking the drug should be up to 7 days, including days of skipping pills; Dragee administration should be started from the next package.

If the dragee is missed and the patient does not have menstrual bleeding during the first usual break in taking the dragee, the probability of pregnancy should be excluded.

Recommendations for violations of the gastrointestinal tract

In severe gastrointestinal disorders, incomplete absorption of the drug is possible; in this case, additional contraceptives should be used.

If vomiting occurs within 3-4 hours after taking the dragee, it is advisable to use the recommendations regarding skipping the dragee. If a woman does not want to change her usual regimen, she needs to take extra dragees from another package.

How to change the time of the appearance of menstruation or how to delay menstruation

To delay the appearance of menstruation, you should continue to take Diane-35 pills from a new package and not take a break in taking the drug. If desired, the period of admission can continue until the end of the second package. At the same time, breakthrough bleeding or hemorrhage cannot be ruled out. The usual intake of the drug is restored after a 7-day break in taking dragees.

To shift the time of the onset of menstruation to another day of the week, it is recommended to shorten the break in taking dragees by the desired number of days. It should be noted that the shorter the break, the more often the absence of menstrual-like bleeding and breakthrough bleeding or hemorrhage during the administration of dragees from the second package (as in the case of delayed menstruation).

Contraindications

PDA should not be used in the presence of at least one of the following conditions or diseases. if any of these conditions or diseases occurs for the first time during the use of the PDA, the drug should be stopped immediately.

Venous or arterial thrombotic / thromboembolic events (e.g. deep vein thrombosis, pulmonary embolism, myocardial infarction) or cerebrovascular disorders currently or in history.

The presence at present or in a history of prodromal symptoms of thrombosis (transient disturbance of cerebral circulation, angina pectoris).

Migraine with focal neurological symptoms in history.

Diabetes mellitus with vascular disease.

The presence of severe or multiple risk factors regarding venous or arterial thrombosis can also be a contraindication (see SPECIAL INSTRUCTIONS).

Pancreatitis is currently or in history if it is associated with severe hypertriglyceridemia.

The presence at present or in the anamnesis of severe liver diseases until indicators of liver function are normalized.

Tumors of the liver (benign or malignant) - diagnosed or history of.

Diagnosed or suspected malignant tumors (such as genitals or mammary glands) that are dependent on sex hormones.

Vaginal bleeding of unknown etiology.

Diagnosed or suspected pregnancy.

Hypersensitivity to active substances or to any component of the drug.

The drug Diane-35 is not prescribed for men.

Side effects

Side effects have been reported with the use of Diane-35, however, their relationship with the use of the drug is neither confirmed nor disproved:

special instructions

Clinical data relates