Mercilon tabs #21

Mercilon

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Composition

One tablet contains 20 μg of ethinylestradiol and 150 μg of desogestrel.In addition: colloidal silicon dioxide, lactose, α-tocopherol, magnesium stearate, potato starch, stearic acid, povidone.

Form of issue

Mercilon is produced in the form of tablets of 21 pieces per blister. Secondary packaging may contain 1, 3 or 6 blisters.

pharmachologic effect

Contraceptive, estrogen-progestogen.

Pharmacodynamics and pharmacokinetics

Mercilon is a combined contraceptive (contraceptive) drug that includes estrogen and progestogen. Contraceptive effectiveness of Mercilon, as well as of other combined oral contraceptives (COCs), is primarily based on its ability to suppress ovulation and increase the release of cervical mucus.The action of the synthetic analogue of estradiol - ethinyl estradiol is to regulate the menstrual cycle simultaneously with the hormone of the yellow body.Effects of gestagen - desogestrel are directed to inhibition of pituitary synthesis by LH and FSH, which leads to prevention of ripening of the follicle, thereby blocking ovulation.In addition to these peripheral and central mechanisms of action of the drug, preventing the maturation of the egg ready for fertilization, there is a contraceptive effect caused by an increase in the viscosity of mucus enveloping the cervix, thereby creating conditions for relative obstruction of spermatozoa through it.In addition to contraceptive effects, Mercilon exhibits a number of properties that can be considered when choosing a contraceptive method. When taking the drug, menstruation-like events are characterized by greater regularity, less pain and weaker bleeding, which reduces the frequency of manifestations of iron deficiency anemia. Also, when taking COC, a reduction in the risk of developing endometrial and ovarian cancer was noted.

Ethinylestradiol

With oral intake, there is a rapid and complete absorption of ethinyl estradiol in the digestive tract. The peak of the plasma concentration of the drug, about 80 pg / ml, occurs in 60-120 minutes. Absolute bioavailability, due to the presystemic conjugation of ethinylestradiol and the first stage of its metabolism, is approximately 60%.In the blood plasma, ethinyl estradiol is not specifically but fairly strongly bound by albumin (an average of 98.5%), which leads to an increase in the plasma level of SHBG. Apparent Vd of the drug is approximately 5 l / kg.In the human body, ethinyl estradiol undergoes the stages of presystemic conjugation, initially in the mucosa of the small intestine, and later in the liver. The primary metabolism of ethinylestradiol occurs with the help of aromatic hydroxylation, in which a large number of various methylated and hydroxylated metabolites are released, present in the form of free metabolic products and conjugates with sulphates and glucuronides. Metabolic clearance proceeds at a rate of approximately 5 ml / min / kg.Reduction of the plasma level of ethinyl estradiol passes two phases. In the final phase, the distribution of the drug is characterized by T1 / 2, lasting approximately 24 hours. Unmodified ethinyl estradiol is not excreted. The products of the drug metabolism are excreted with bile and urine in a ratio of 6: 4. T1 / 2 metabolites are approximately 24 hours.Equilibrium concentrations of ethinylestradiol are observed in plasma after 3-4 days, when its plasma concentration is 30-40% higher than the same value observed for a single dose.

Desogestrel

Orally taken desogestrel is quickly and fully absorbed into the digestive tract, after which its transformation occurs etonogestrel. The plasma peak concentration is approximately 2 mg / ml and is observed after approximately 90 minutes after a single dose. Bioavailability is at the level of 62-81%.Formed etonogestrel combines with plasma proteins albumin and globulin (SHBG), which binds sex hormones. Thus, 40-70% of this isnogestrel is specifically associated with SHBG and only 2-4% of the total plasma fraction of the drug is present in the form of a free steroid. The increase in the level of SHBG induced by ethinylestradiol affects the distribution between plasma proteins, resulting in a decrease in the albumin-bound portion of the drug and an increase in its SHBG-bound fraction. Vd desogestrel reaches about 1.5 l / kg.Complete metabolic transformations of etonogestrel occur by a specific way of steroid metabolism. The rate of metabolic plasma clearance is approximately 2 ml / min / kg. Interactions with ethinylestradiol taken in parallel were not detected.Decrease in the plasma level of etonogestrel occurs in two phases. In the final phase, the distribution of the drug is characterized by T1 / 2, which is approximately 30 hours. Desogestrel, like the products of its metabolism, is excreted with bile and urine in an approximate ratio of 4: 6.The pharmacokinetics of etonogestrel directly depends on the concentration of SHBG, which is tripled by exposure to ethinylestradiol. With the daily reception of Mercilon, the plasma level of etonogestrel rises by about 2-3 times and reaches the equilibrium state in the second half of the course.

Pre-clinical safety information

To assess the possible risks to humans, the toxic effects of ethinylestradiol and desogestrel, as well as their combinations, were carried out on animals. In the course of systematic testing of the tolerability of these drugs when they were used again, no phenomena were found that indicated an unexpected toxic risk to the human body. When analyzing the long-term toxicity of taking repeated doses of drugs, their oncogenic potential was not noted. Nevertheless, the ability of sex steroids to accelerate the growth of tumors and certain hormone-dependent internal tissues of the body should be taken into account.Studies of possible teratogenicity and embryotoxicity and evaluation of the effects of both drugs on lactation of animals, fecundity, fetal formation and development, the ability of their offspring to reproduce did not give rise to the suspicion of the possibility of such negative phenomena in humans when applying the recommended dosages of drugs. In vitro and in vivo studies have not revealed any of their mutagenic potential.

Indications for use

The monthly course for taking Mercilon tablets is indicated for contraception.

Contraindications

Mercilon is absolutely contraindicated in:    severe liver diseases, including history of them (up to the absolute normalization of liver function)    venous thrombosis, present or present in the past, including pulmonary embolism (PE) and deep vein thrombosis (DVT)    hepatic tumors of any etiology (benign or malignant), including indications of their development in the past    arterial thrombosis, observed in the present or present in the past (including stroke and myocardial infarction) or disease states that are risk factors for the formation of thrombosis (including angina pectoris and transient ischemic heart disease)    pregnancy (including cases of alleged pregnancy)    vaginal bleeding of unclear etiology    breastfeeding    propensity to arterial or venous thrombosis, including cases of protein C or S deficiency, resistance to activated protein C, deficiency of antithrombin III, hyperhomocysteinemia, the presence of antiphospholipid antibodies (cardiolipin antibodies and lupus anticoagulant)    intolerance to sugars    migraine in anamnesis, occurring with neurologic focal symptoms    personal hypersensitivity    diabetes mellitus, accompanied by vascular lesion    nicotine dependence in the age after 35 years (when smoking a day more than 15 cigarettes)    presence of multiple or severe risk factors for the formation of thrombosis (including arterial hypertension with fixation of blood pressure at 160/100 mm Hg or more)    malignant hormone-dependent formations found in the mammary glands or genitals (including suspicions of them)    pancreatitis, observed in the present or present in the past, flowing with severe hypertriglyceridemia.In the event of any of the abovementioned painful conditions when using Mercilon, a woman should immediately stop taking pills and seek medical help.If any of the following risk factors / conditions are currently identified, the physician must carefully weigh the expected benefits of taking Mercilon tablets and the potential risk of adverse effects on women and prescribe the drug with extreme caution when:    atrial fibrillation    hemolytic-uremic syndrome    nicotine addiction    tracing in the family history of serious thromboembolic pathologies (thromboembolism / venous or arterial thrombosis observed in parents, siblings at a relatively young age)    hereditary sickle-cell anemia    Obesity (with a weight index of more than 30 kg / m2)    hypertriglyceridemia (including an indication of it in a family history)    dyslipoproteinemia    chronic and acute hepatic diseases, inclusive with congenital hyperbilirubinemia (Dubin-Johnson syndrome, Gilbert, Rotor syndrome)    arterial hypertension    inflammatory chronic bowel pathologies (including ulcerative colitis and Crohns disease)    manifestations of migraine    systemic lupus erythematosus    valvular heart defects    diabetes mellitus    changes in biochemical parameters that may represent markers of acquired or congenital propensity to thrombosis (including cases of protein C or S deficiency, resistance to activated protein C, antithrombin III deficiency, hyperhomocysteinemia, the presence of antiphospholipid antibodies (cardiolipin antibodies and lupus anticoagulant)    superficial thrombophlebitis, varicose veins (due to the unclear role of these disease states in the formation of venous thromboembolism)    prolonged forced immobilization, performing surgical operations on the lower extremities or extensive areas of the body, severe injuries (in the event that when receiving Mercilon conditions requiring the above surgical operations or prolonged immobilization, discontinue use of the drug, and during planned surgical operations to suspend his admission for 4 weeks before intervention and 2 weeks after remobilization)    in the postpartum period and at the age of 35 years.

Side effects

Mercilon's birth control pills sometimes lead to the following side effects:    thromboembolism or thrombosis (including thromboembolism of retinal arteries, mesenteric, hepatic, renal veins and arteries, myocardial infarction, PE, stroke, DVT)    headache    erythema nodosum    increased blood pressure    discharge from the mammary glands / vagina    liver tumors    stomach ache    mammary cancer    erythema multiforme    bloody acyclic vaginal discharge (mostly during the first months of use)    Chloasma (especially if it is present during the previous pregnancy)    allergic reactions    decreased / increased libido    hypersensitivity    hives    increase / decrease in weight    skin rash    fluid retention    nausea, vomiting    intolerance to contact lenses    depression    migraine    change of mood    increase / soreness of the mammary glands.

Mercilon Contraceptive Pills, Instructions for Use

Mercilon tablets are indicated for oral administration in the order indicated on the blister. Instructions for use Mercilon prescribes to women daily intake of one tablet for 21 days, preferably at a certain time of the day, washing down, if necessary, with a small amount of water. The beginning of taking tablets from the next blister should be done after a 7-day interval, during which menstrual bleeding should occur. The appearance of menstrual bleeding, as a rule, is observed on the 2-3 day of the end of tablets in the blister used and can continue with the taking of tablets from the subsequent blister.

Start of reception of Mercilon

If a woman did not take hormonal contraceptives for the last 30 days, it is better to take Mercilone on the first day of menstruation. Also, it is possible to start taking these contraceptive pills on the 2nd-5th day of menstruation, but during the 7 days of the first cycle it is recommended to use an auxiliary barrier (caps, condoms) method of contraception.When switching to Mercilon from other hormonal combination contraceptives (transdermal patches, vaginal rings, other COCs), it is advisable to start taking Mercolone tablets the next day after the last use of the previous contraceptive method / remedy, but not later than the next day following the usual break, accompanied by menstrualnopodobnym bleeding.In case of correct and consistent use by a woman of the previous contraceptive method / means and with reliable information on the absence of pregnancy, you can go to Mercilon on any convenient day of the cycle. Please note that the mandatory interval when using the previous method / contraceptive method should not be more than the recommended one.    Go to Mercilon with a mini-drink can be on any convenient day    with the IUD or implant - on the day of their removal    with contraceptive injections - at the time of the next injection.In all the cases described above, during the first 7 days of applying Mercilon, barrier contraceptives should be used.After an abortion in the first trimester, you can start taking Mercilone immediately, without the use of any contraceptives.After an abortion or birth in the second trimester, it is recommended to start taking Mercilone after 21-28 days. If you need a later application of Mercilon, during the first 7 days you need to use barrier contraceptives. When a woman makes sexual contacts during the period of non-use of contraceptives, before taking Mercilon, you should make sure she is not pregnant or wait for menstruation.

Algorithm of actions when missing the next pill

With a 12-hour delay in taking the nearest pill, the reliability of the contraceptive effect of Mercilon does not decrease. The required tablet must be taken in a 12-hour period and then follow the generally accepted intake schedule.If the next tablet is delayed for more than 12 hours, the reduction in the contraceptive effect of Mercilon is possible. In this case, the woman should be guided by the following two rules:    never stop taking pills for more than 7 days    remember that adequate oppression of the hypothalamic-pituitary-ovarian system requires a continuous 7-day tablet administration.The cyclic scheme of the use of Mercilon means the use of tablets for 3 weeks, so that the following recommendations for the resumption of taking the tablets after they are missed will be appropriate.

First week

The required tablet should be taken to a woman in the nearest time period, even if 2 tablets are taken concurrently, followed by a generally accepted intake schedule. In addition, barrier contraceptives should be used in the first 7 days. When a woman has sex during the previous 7 days, a probable pregnancy should be excluded. The risk of pregnancy increases with the number of missed tablets and with the approaching interval time in their intake.

The second week

The required tablet should be taken to a woman in the nearest time period, even if 2 tablets are taken concurrently, followed by a generally accepted intake schedule. With the timely intake of all previous tablets during the previous 7 days before the missed dose, you can not resort to additional use of other contraceptives / methods. Otherwise, or if more than one tablet is skipped, barrier contraceptives should be used within the next 7 days.

The third week

It is possible to decrease the reliability of the contraceptive effect due to the approach of the interval in taking the tablets. This situation can be avoided by adapting the contraceptive regimen. When using any of the two schemes listed below, it is possible not to resort to additional use of other contraceptives, with the timely intake of all previous tablets during the previous 7 days prior to the missed dose. In case of violation of the standard reception of tablets, it is recommended to use the first scheme below, with barrier contraceptives being used for the next 7 days.

Recommended regimens for adjusting the intake of tablets when they are skipped during the third week

    The required tablet should be taken to a woman in the nearest time period, even if 2 tablets are taken concurrently, followed by a generally accepted intake schedule. Tablets from a new blister need to start drinking immediately after they end in the previous blister, without taking into account the 7-day interval. In this case, the possibility of developing menstrual bleeding is extremely small, but some women may have spotting (abundant or smearing).    It is possible to recommend a woman to completely stop taking tablets from the blister used for a period of up to 7 days (including the interval time), and then proceed to receive tablets from the new blister.In the absence of menstrual bleeding during the nearest interval in taking the tablets with their previous pass, the probability of pregnancy should be taken into account.

Precautions for gastrointestinal disorders

If a woman develops severe gastrointestinal disorders, the absorption of active ingredients of Mercilon may occur in an incomplete volume, which requires an additional use of barrier contraceptives. When vomiting occurs within 3-4 hours after taking the pill, it is necessary to follow the algorithm of actions recommended when missing the next pill or take an additional pill from another blister.

Changing the timing of the menstrual cycle

To delay menstruation, continuous use of tablets from two blisters is necessary, without taking into account the 7-day interval. This allows you to delay menstruation for any desired period of time until the full use of the second blister. During this period, some women may have spotting (abundant or smearing). Renewal of normal conventional drug administration is possible after a mandatory 7-day interval.To shift the menstruation to the desired day of the week, you need to reduce the usual 7-day interval for the required number of days (from 1 to 6). The smaller the interval, the greater the risk of the absence of menstrual bleeding and the appearance of bloody discharge (heavy or smearing) when taking tablets from a subsequent blister.

Overdose

With the simultaneous administration of a large number of Mercilon tablets, there may be the occurrence of nausea, sometimes resulting in vomiting, as well as bloody vaginal discharge in young girls. There were no serious adverse effects of taking excessive doses of Mercilon. Treatment is symptomatic.

Interaction

It should be remembered that against the background of a continuous intake of oral contraceptives, the use of other medications can lead to a decrease in the effectiveness of contraceptives, as well as the occurrence of acyclic bleeding.During the course of the course of COC, the parallel use of inducers of microsomal hepatic enzymes (preparations of St. John's Wort, Griseofulvin, phenytoin, felbamate, barbiturates, ritonavir, primidon, Topiramate, carbamazepine, rifabutin, rifampicin, oxcarbazepine, etc.) can increase the clearance of sex hormones. At 2-3 weeks of taking Mercilon, the peak induction of liver enzymes may not be observed, but only after the interval in taking the medication tablets by the end of the 4th week.There are also reports of a decrease in the contraceptive efficacy of Mercilon with a combined intake of antibiotics belonging to the groups of tetracyclines and ampicillins, with an unexplained mechanism of interaction.In the case of a woman taking a COC of any of the aforementioned remedies, she is advised to additionally use barrier contraceptives or completely switch to another contraceptive method / remedy. When combined use of inducers of hepatic enzymes, barrier contraceptives should be used throughout the course of the therapeutic course, and also for the next 28 days. If long-term therapy with inducers of hepatic enzymes is necessary, a woman should better switch to another contraceptive / method.In the case of a woman taking COC, antibiotics (with the exception of the properties of Griseofulvin and Rifampicin, which are similar to those of hepatic enzyme inducers), it is necessary to use barrier contraceptives throughout the entire therapy phase and also for the next 7 days. With the continuation of the time period for the use of barrier contraceptives after taking all the COC tablets in the blister used, it is necessary to start taking the tablets from the subsequent blister without taking into account the 7-day interval.Oral contraceptives are also able to affect the metabolic transformations of other medications and, accordingly, change their plasma and tissue concentrations, for example, lower in Lamotrigine and increase in Ciclosporin.If it is necessary to use other medicines by the woman who takes COC, the official instruction for their use should be followed.

Storage conditions

Mercilon tablets should be stored in a factory blister, in a dark, dry room, with a temperature of 2-30 ° C.Shelf life - 3 years from the date of issue.

special instructions

If a woman has any of the following risk factors or illnesses, careful consideration should be given to weighing the benefits and likely risks of using Mercilon contraceptive pills. All possible negative consequences of taking COC should be explained to the patient before the drug is started. If you see an exacerbation of existing diseases or worsening of risk factors or illnesses, a woman must immediately consult a doctor to resolve the issue of stopping or further taking Mercilon.

Lactose

Women with any hereditary sugar intolerance should take into account the 80 mg lactose contained in one Mercilon tablet.

Diseases of the vascular system

In conducting epidemiological studies, there was a suspicion of a possible connection between the use of Mercilon and an increased risk of thrombotic and thromboembolic arterial and venous pathologies (including myocardial infarction, DVT, stroke, PE).Taking any drug from the COC group increases the risk of venous thromboembolism, which can manifest itself as PE and DVT (sometimes fatal). An increased risk of these pathologies is observed in the first 12 months of COC use.Some epidemiological studies have shown an increased risk of venous thromboembolism in women taking low-dose COCs, including the third generation of progestogens, including desogestrel, compared with women taking low-dose COCs including levonorgestrel progestogen.Occasionally, thrombosis may occur in other blood vessels (including arteries and veins of the liver, retina, mesentery, brain or kidney). There is no consensus on the relationship between the use of COCs and the onset of thrombosis.An increase in the intensity and frequency of migraine attacks on the background of Mercilon, which may be a symptom of cerebrovascular disorders, gives rise to an immediate cessation of the use of this contraceptive.

Tumor Education

The most significant risk factor for the formation of cervical cancer is the persistence of human papillomavirus (HPV infection). Some epidemiological studies have documented an increase in the likelihood of developing cervical cancer with long-term admission of COCs by women. Until now, there is no consensus on the extent to which these secondary mixing factors influence the data, including an increase in the number of screening tests of the cervix and the specificity of sexual behavior, including the use of barrier contraceptives, or their interrelationships.There is evidence of a slight increase in the relative risk (approximately 1.24 times) of the formation of breast cancer in women with COCs. This increased risk is systematically reduced for 10 years after the end of the COC application. In view of the fact that in women under 40 years, breast tumors are rare, the increase in the probability of formation of this pathology in women taking COC at the moment, or recently stopped their use, is small, compared with the initial likelihood of such a cancer. The increased risk of breast cancer in women using COCs can be explained by earlier diagnoses of such cancers, the biological effects of COCs themselves, and a combination of these factors.There is a trend according to which, in women who have ever used COC, breast cancer is clinically less neglected than that of women using other contraceptive methods / means.With the use of Mercilon, cases of the appearance of benign, even less often malignant, hepatic neoplasms were extremely rare. In some cases, these tumors were the cause of intra-abdominal bleeding, a life threatening condition. The doctor needs to take into account the probability of having a hepatic tumor in the differential diagnosis of pathologies in a woman taking Mercilon in case of symptoms, including: a liver enlargement, acute pain at the top of the abdomen, signs of intra-abdominal bleeding.

Other diseases

In case of diagnosing a woman, or even members of her closest family, hypertriglyceridemia with Mercilon, there may be an increased risk of pancreatitis.In the event of persistent arterial hypertension, the woman taking Mercilon should stop taking the drug and begin therapy of arterial hypertension. In the case of complete stabilization of blood pressure as a result of antihypertensive therapy, consideration may be given to resuming the use of Mercilon.There is an opinion that itching and / or jaundice caused by cholestasis formation of concrements in the gallbladder systemic lupus erythematosus herpes pregnant porphyria chorea hemolytic-uremic syndrome angioedema (hereditary) hearing loss caused by otosclerosis is formed or aggravated in both pregnant women and women taking Mercilone. In the latter case, the evidence of the connection of the above-described disease states with the use of the drug Mercilon seems unconvincing.The occurrence of any violations of the hepatic function observed during the reception of Mercilon, can be considered as a basis for drug discontinuation, up to the normalization of the parameters of the hepatic function. The occurrence of cholestatic jaundice, previously observed when taking sexual hormones or pregnancy, requires the termination of the use of Mercilon.Although the effects of Mercilon may interfere with insulin and glucose tolerance, there is no evidence of the need to change the therapeutic regimen for low-dose COCs (including up to 50 μg ethinylestradiol) for patients with diabetes mellitus. However, women with diabetes who take Mercilon require careful medical supervision.There are data linking the formation of ulcerative colitis and Crohn's disease with the systemic use of COCs, including Mercilon.In some cases, with the use of Mercilon, the appearance of chloasma (pigmentation on the skin of the face) was observed, especially when it developed during a previous pregnancy. In case of taking Mercilon by women predisposed to chloasma, they should avoid any (natural or artificial) exposure to ultraviolet radiation.

Medical consultations / examinations

Before the appointment of Mercilon, or the resumption of its use, the doctor must conduct a full examination, involving the taking of a woman's drug, to collect her medical history, as well as a family anamnesis. The list of necessary surveys and the frequency of their conduct should be selected individually and in accordance with generally accepted practice and be conducted at least once every six months.The woman is obliged to carefully study the official instruction on the application of Mercilon and strictly follow the recommendations prescribed in it.A woman should be informed about the inability of oral contraceptives to resist sexual infections, including HIV (AIDS).

Decreased efficiency

A woman should remember that the effectiveness of the contraceptive effect of Mercilon can decrease with the miss of another pill, the occurrence of gastrointestinal disorders and the concurrent administration of certain medications.

Bloody issues

With the use of Mercilon, especially in the first months, there may be irregular bloody discharge (abundant or smearing). In this regard, the assessment of irregular bleeding should be carried out after the adaptation period, which usually takes 3 months.If irregular bleeding persists or occurs after the previous regular cycles, it is necessary to consider possible nonhormonal factors of the disorder of the usual cycle and to assign appropriate tests to exclude pregnancy (possibly diagnostic scraping) and malignant neoplasms.In some women, there is no menstrual bleeding during the mandatory interval between taking tablets from different blisters. In the case of a woman's conscientious implementation of all the recommendations for the use of Mercilon, the probability of her pregnancy is extremely low. Otherwise, and in the absence of bleeding during 2 consecutive cycles, you should exclude a probable pregnancy.

Laboratory research

The use of oral contraceptives may adversely affect the performance of individual laboratory tests, including biochemical indicators of kidney / liver function, adrenal gland function, thyroid gland function serum level of transport proteins (in particular, corticosteroid-binding globulin and lipid / lipoprotein fractions) parameters of coagulation, carbohydrate metabolism and fibrinolysis. As a rule, such changes do not go beyond permissible deviations in the results of laboratory indicators.

Analogues

    Logest    Yaz    Yarina    Midiana.

Children

Indication for the use of Mercilon is contraception, in connection with which, the use of this drug in pediatrics is not appropriate.

In pregnancy and lactation

Pregnant women should not take Mercilon. When pregnancy occurs during the period of application of Mercilon, it is necessary to interrupt the reception of the drug tablets. The detailed studies conducted did not reveal an increase in the likelihood of birth defects in infants whose mothers were taking COCs prior to the onset of pregnancy, as well as the teratogenic effects of COCs in case of their unintended use at the beginning of pregnancy.The effects of Mercilon can affect lactation by changing the composition and amount of breast milk, as well as releasing a number of sex steroids and / or metabolic products with it. In this regard, Mercilon is contraindicated in breastfeeding.

Reviews of Mercilon

The doctors' comments on the Mercilon contraceptive pill regarding their effectiveness, in case of regular admission and accurate performance by the woman of all other recommendations, are entirely positive, which is confirmed by all patients using this medication as a contraceptive. On the other hand, this contraceptive, due to concomitant diseases / conditions and individual characteristics of the body, is not suitable for every woman. When taking Mercilon, it is not uncommon to find references to the formation of various negative side effects (decreased libido, depression, headaches, rash, chloasma) or increased symptoms of existing pathologies (pancreatitis, thrombosis, migraine), in some cases leading to withdrawal of the drug.

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