Josegood film-coated tablets 3 mg/0.02 mg blister No. 28

Instructions Josegood film-coated tablets 3 mg/0.02 mg blister No. 28

Composition

active ingredients: drospirenone, ethinylestradiol;

1 tablet contains drospirenone 3 mg and ethinyl estradiol 0.02 mg;

excipients: lactose, monohydrate; polacrilin potassium; povidone K30; magnesium stearate; shell: OpadryIIPink 85F34048 film-coating mixture: polyethylene glycol (macrogol); titanium dioxide (E 171); polyvinyl alcohol partially hydrolyzed; talc; iron oxide red (E 172), iron oxide yellow (E 172);

1 placebo tablet contains: lactose, monohydrate; polacrilin potassium; povidone K30; silicon dioxide colloidal anhydrous; magnesium stearate; shell: OpadryIIWhite 85F18422 film-coating mixture: polyethylene glycol (macrogol); titanium dioxide (E 171); polyvinyl alcohol partially hydrolyzed, talc.

Dosage form

Film-coated tablets.

Main physicochemical properties: cylindrical tablets with a biconvex surface, coated with a pink film coating, and placebo tablets with a cylindrical shape with a biconvex surface, coated with a white film coating.

Pharmacotherapeutic group

Hormonal contraceptives for systemic use. Progestogens and estrogens, fixed combinations. ATX code G03A A12.

Pharmacological properties

Pharmacodynamics.

Pearl Index of Contraceptive Failure: 0.41 (upper two-sided 95% confidence interval: 0.85). Total Pearl Index (contraceptive failures + patient errors): 0.80 (upper two-sided 95% confidence interval: 1.30).

The contraceptive effect of the drug Josegood is based on the interaction of various factors, the most important of which are the suppression of ovulation and changes in cervical secretion.

In a three-cycle clinical trial of ovulation suppression comparing drospirenone 3 mg/ethinyl estradiol 0.02 mg in a 24-day regimen with a 21-day regimen, the 24-day regimen was associated with greater suppression of follicular development. After intentional dosing errors during the third cycle of therapy, a greater majority of women on the 21-day regimen experienced ovarian activity, including ovulation, compared with women on the 24-day regimen. Ovarian activity returned to pre-treatment levels within the post-therapy cycle in 91.8% of women on the 24-day regimen.

The drug Josegood® is a combined oral contraceptive with ethinylestradiol and the progestogen drospirenone. In therapeutic doses, drospirenone exhibits antiandrogenic and moderate antimineralocorticoid properties. It does not have estrogenic, glucocorticoid and antiglucocorticoid activity. Therefore, drospirenone has a similar pharmacological profile to natural progesterone.

According to clinical studies, the moderate antimineralocorticoid properties of Josegood® result in a moderate antimineralocorticoid effect.

Two multicenter, double-blind, randomized, placebo-controlled studies were conducted to evaluate the efficacy and safety of Josegood® in women with moderate acne vulgaris. After 6 months of treatment, compared with placebo, the drug demonstrated a statistically significant reduction of 15.6% (49.3% vs. 33.7%) in the number of inflammatory elements, 18.5% (40.6% vs. 22.1%) in the number of non-inflammatory elements, and 16.5% (44.6% vs. 28.1%) in the total number of lesions. Also, a higher percentage of subjects, 11.8% (18.6% vs. 6.8%), had “clear” and “almost clear” skin, as assessed by the ISGA (Investigator's Stated Global Assessment) scale.

Pharmacokinetics

Drospirenone

Absorption. Orally administered drospirenone is rapidly and completely absorbed. The maximum serum concentration of 38 ng/ml is reached approximately 1-2 hours after a single oral dose. Bioavailability is 76-85%. Simultaneous food intake does not affect the bioavailability of drospirenone.

Distribution. After oral administration, the concentration of drospirenone in the blood serum decreases with a mean terminal half-life of about 31 hours. Drospirenone binds to serum albumin, but not to GH and corticoid-binding globulin. Only 3-5% of its total amount in the blood serum is present in the free state. The increase in GH caused by ethinylestradiol does not affect the binding of drospirenone to serum proteins. The mean volume of distribution of drospirenone is 3.7 ± 1.2 l/kg.

Metabolism: Drospirenone is extensively metabolized after oral administration. The main metabolites in plasma are the acid forms of drospirenone, formed by opening the lactone ring, and 4,5-dihydro-drospirenone-3-sulfate, formed by hydration with subsequent sulfation. Drospirenone is also subject to oxidative metabolism catalyzed by CYP3A4. In vitro, drospirenone may weakly or moderately inhibit the cytochrome P450 enzymes: CYP1A1, CYP2C9, CYP2C19 and CYP3A4.

Steady state. During the application cycle, the maximum steady-state concentration of drospirenone in serum, which is approximately 70 ng/ml, is reached after 8 days of use. Drospirenone levels in the blood accumulated 3-fold as a result of the ratio of the terminal half-life and the dosing interval.

Certain groups of patients

Women with renal impairment. Steady-state serum concentrations of drospirenone in women with mild renal impairment (creatinine clearance 50-80 ml/min) were comparable to those in women with normal renal function (creatinine clearance >80 ml/min). Serum drospirenone levels were on average 37% higher in women with moderate renal impairment (creatinine clearance 30-50 ml/min) than in women with normal renal function. Drospirenone was well tolerated in all patient groups. Drospirenone has been shown to have no clinically significant effect on serum potassium.

Women with impaired liver function.

In a single-dose study, oral clearance of drospirenone was reduced by approximately 50% in subjects with moderate hepatic impairment compared with volunteers with normal liver function. The observed difference in clearance of drospirenone in subjects with moderate hepatic impairment did not result in any significant differences in serum potassium levels. Even in the presence of diabetes mellitus and concomitant spironolactone therapy (two factors that can induce hyperkalemia), no increase in serum potassium above the upper limit of normal was observed. It can be concluded that drospirenone is well tolerated in subjects with mild to moderate hepatic impairment (Child-Pugh class B).

Ethnic groups: No clinically significant differences in the pharmacokinetics of drospirenone or ethinyl estradiol were observed between Japanese and Caucasian women.

Ethinylestradiol

Absorption. Ethinylestradiol is rapidly and completely absorbed after oral administration. Peak serum concentrations of 33 pg/ml are reached within 1-2 hours after a single oral dose. Absolute bioavailability due to presystemic conjugation and first-pass metabolism is approximately 60%. Concomitant food intake reduces the bioavailability of ethinylestradiol in approximately 25% of subjects, while remaining unchanged in the remainder.

Distribution: Serum ethinylestradiol levels decline in a biphasic manner, with a terminal half-life of approximately 24 hours. Ethinylestradiol binds strongly but nonspecifically to serum albumin (approximately 98.5%) and induces an increase in serum concentrations of GH and CSH. The apparent volume of distribution is approximately 5 l/kg.

Metabolism: Ethinylestradiol is extensively metabolized in the gastrointestinal tract and during the first pass through the liver. Ethinylestradiol is metabolized mainly by hydroxylation of the aromatic ring with the formation of a wide range of hydroxylated and methylated metabolites, which are present in the free state and as conjugates with glucuronides and sulfates. The metabolic clearance of ethinylestradiol is approximately 5 ml/min/kg.

In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1, and CYP1A2, and based on its mechanism of action, an inhibitor of CYP3A4/5, CYP2C8, and CYP2J2.

Excretion. Ethinylestradiol is practically not excreted unchanged. Metabolites of ethinylestradiol are excreted in urine and bile in a ratio of 4:6. The half-life of metabolites is almost 1 day.

Steady state. Steady state is reached in the second half of the cycle of use, when the concentration of ethinylestradiol in the blood serum increases by 2.0-2.3 times.

Preclinical safety data.

In laboratory animals, the effects of drospirenone and ethinylestradiol were limited to those associated with the known pharmacological action. In particular, studies on reproductive toxicity in animals showed species-specific embryotoxic and fetotoxic effects. At exposures exceeding those observed in users of Josegood®, effects on sexual differentiation were observed in some animal species. Studies on ecological risk assessment showed that ethinylestradiol and drospirenone may potentially pose a threat to the aquatic environment (see section "Special precautions").

Indication

Oral contraception.

Contraindication

Combined hormonal contraceptives (CHCs) should not be used if any of the following conditions are present. If any of these conditions appear for the first time during CHC use, the drug should be discontinued immediately.

· Presence or risk of developing venous thromboembolism (VTE).

o venous thromboembolism at present, in particular due to anticoagulant therapy, or in history (e.g. deep vein thrombosis (DVT) or pulmonary embolism (PE));

o major surgical interventions with prolonged immobilization (see section "Peculiarities of use");

o high risk of venous thromboembolism due to the presence of multiple risk factors (see section "Special warnings and precautions for use").

· Presence or risk of arterial thromboembolism (ATE).

o the presence of arterial thromboembolism at present or in history (e.g. myocardial infarction) or the presence of prodromal symptoms (e.g. angina);

o current or history of cerebrovascular disease, presence of prodromal symptoms (e.g. transient ischemic attack (TIA));

o known hereditary or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinemia and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);

o migraine with focal neurological symptoms in history;

o high risk of arterial thromboembolism due to the presence of multiple risk factors (see section "Special warnings and precautions for use") or due to the presence of one serious risk factor, such as:

- diabetes mellitus with vascular complications;

- severe arterial hypertension;

- severe dyslipoproteinemia.

· Presence of severe liver disease at present or in history, until liver function tests have returned to normal.

Severe renal failure or acute renal failure.

· Presence of liver tumors at present or in history (benign or malignant).

Known or suspected malignant tumors (e.g., genital or breast) that are sex hormone-dependent.

· Vaginal bleeding of unknown etiology.

· Hypersensitivity to the active substances or to any of the components of the medicinal product.

Current or past breast cancer, which may be hormone-sensitive [see section “Warnings and precautions”, subsection “Malignant neoplasms”].

The drug Josegood® is contraindicated when used concomitantly with drugs containing ombitasvir/paritaprevir/ritonavir and dasabuvir or glecaprevir/pibrentasvir (see sections “Special instructions” and “Interaction with other medicinal products and other types of interactions”).

Special safety precautions

This medicinal product may pose a risk to the environment (see section 5.1). Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Interaction with other medicinal products and other types of interactions

The information for the concomitant medicinal product should be consulted to identify potential interactions.

Effect of other medicines on Josegood®

Interactions are possible with drugs that induce microsomal enzymes. This will lead to an increase in the clearance of sex hormones, which in turn causes changes in the pattern of menstrual bleeding and/or loss of contraceptive effectiveness.

Therapy

Enzyme induction may be detected after a few days of treatment. Maximum enzyme induction is generally observed after a few weeks. After discontinuation of treatment, enzyme induction may persist for about 4 weeks.

Short-term treatment

Women taking enzyme-inducing drugs should temporarily use a barrier method or another method of contraception in addition to the COC. The barrier method should be used throughout the entire period of treatment with the drug and for 28 days after stopping its use. If therapy is started during the last COC tablet-free period, the next COC tablet-free period should be started immediately after the previous one without the usual tablet-free interval.

Long-term treatment

For women on long-term therapy with active substances that induce liver enzymes, a barrier or other appropriate non-hormonal method of contraception is recommended.

The following interactions have been reported based on published data.

Active substances that increase COC clearance (reduced COC efficacy due to enzyme induction), for example:

barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin; medicines used for HIV infection: ritonavir, nevirapine and efavirenz; also possibly felbamate, griseofulvin, oxcarbazepine, topiramate and herbal medicines containing St. John's wort extract (Hypericum perforatum).

Active substances with inconsistent effects on COC clearance

When used concomitantly with COCs, a large number of combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with hepatitis C virus (HCV) inhibitors, may increase or decrease plasma concentrations of estrogen or progestins. The cumulative effect of such changes may be clinically significant in some cases.

Therefore, the prescribing information for the concomitant HIV/HCV medicinal product should be consulted for potential interactions and any other recommendations. In case of any doubt, women should additionally use a barrier method of contraception during treatment with protease inhibitors or non-nucleoside reverse transcriptase inhibitors.

The clinical significance of the potential interaction with enzyme inhibitors remains unclear.

Concomitant use of strong CYP3A4 inhibitors may increase plasma concentrations of estrogen or progestin, or both.

In a multiple-dose study of the combination of drospirenone (3 mg/day)/ethinyl estradiol (0.002 mg/day) and the strong CYP3A4 inhibitor ketoconazole, administered concomitantly for 10 days, the AUC(0-24h) of drospirenone and ethinyl estradiol increased by 2.7- and 1.4-fold, respectively.

Etoricoxib at doses of 60 to 120 mg/day has been shown to increase plasma concentrations of ethinyl estradiol by 1.4- to 1.6-fold, respectively, when co-administered with a combined hormonal contraceptive containing 0.035 mg ethinyl estradiol.

Effect of Josegood® on other medicines

COCs may affect the metabolism of some active substances. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporine) or decrease (e.g. lamotrigine).

Based on in vivo interaction studies in female volunteers using omeprazole, simvastatin and midazolam as marker substrates, it was found that a clinically significant interaction of drospirenone at a dose of 3 mg with other active substances induced by cytochrome P450 is unlikely.

Clinical data suggest that ethinylestradiol inhibits the clearance of CYP1A2 substrates, which in turn causes a mild (e.g. theophylline) or moderate (e.g. tizanidine) increase in their plasma concentrations.

Pharmacodynamic interactions

Concomitant use with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, or glecaprevir/pibrentasvir increases the risk of alanine aminotransferase (ALT) elevations (see sections 4.3 and 4.4).

Therefore, women using Josegood® should temporarily switch to an alternative method of contraception (e.g. progestogen-only contraceptives or non-hormonal methods) before starting therapy with this combination of drugs. Josegood® can be resumed 2 weeks after completing therapy with this combination.

In patients with normal renal function, concomitant use of drospirenone and ACE inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs) has not shown a significant effect on serum potassium levels. However, concomitant use of Josegood® and aldosterone antagonists or potassium-sparing diuretics has not been studied. In this case, serum potassium levels should be monitored during the first treatment cycle (see also section "Special warnings and precautions for use").

Other forms of interaction

Laboratory tests

The use of contraceptive steroids may affect the results of some laboratory tests, such as biochemical parameters of liver, thyroid, adrenal and renal function, plasma concentrations of transport proteins such as corticosteroid-binding globulin, plasma concentrations of lipid/lipoprotein fractions, and parameters of carbohydrate metabolism, coagulation and fibrinolysis. These changes are usually within normal limits. Drospirenone increases plasma renin and aldosterone activity, which is induced by its moderate antimineralocorticoid activity.

Application features

The decision to prescribe Josegood® should take into account the woman's individual current risk factors, including risk factors for venous thromboembolism (VTE), and the risk of VTE associated with Josegood® compared with other combined hormonal contraceptives (CHCs) (see sections "Contraindications" and "Special Instructions").

Warning

If any of the conditions or risk factors listed below are present, the appropriateness of using Josegood® should be discussed with the woman.

In case of exacerbation or at the first manifestations of any of the above conditions or risk factors, women are advised to consult a doctor and determine the need to discontinue taking the drug Josegood®.

In case of suspected or confirmed VTE or ATE, CHC use should be discontinued. If anticoagulant therapy is initiated, alternative adequate contraception should be provided due to the teratogenic effects of anticoagulants (coumarins).

Circulatory disorders

The use of any CHC increases the risk of venous thromboembolism (VTE) in women who use it compared with those who do not use it. Medicines containing levonorgestrel, norgestimate or norethisterone are associated with a lower risk of VTE. The use of other medicines such as Josegood® may lead to a twofold increase in the risk. The decision to use medicines other than those with the lowest risk of VTE should only be made after discussion with the woman. It is necessary to ensure that she is aware of the risk of VTE associated with the use of Josegood®, the extent of the influence of her existing risk factors and the fact that the risk of VTE is highest during the first year of use. There is some evidence that the risk of VTE may increase when CHC use is resumed after a break of 4 weeks or more.

Two in 10,000 women who are not taking CHCs and are not pregnant will develop a VTE in a year. However, the risk for an individual woman may be much higher depending on the risk factors she has (see below).

It has been estimated1 that out of 10,000 women using a CHC containing drospirenone, 9 to 12 will develop a VTE in one year. This compares with 62 in women using a CHC containing levonorgestrel.

In both cases, the number of VTE cases per year was lower than would normally be expected during pregnancy or in the postpartum period.

VTE can lead to fatal outcomes in 1-2% of cases.

Number of VTE cases per 10,000 women in one year

1 These figures are based on all epidemiological data, taking into account the relative risks associated with the use of different CHCs compared with the use of CHCs containing levonorgestrel.

2 On average 5-7 cases per 10,000 women-years based on the calculation of the relative risk of using levonorgestrel-containing CHCs compared to that in women not using CHCs (approximately 2.3 - 3.6 cases).

Risk factors for developing VTE

The risk of developing venous thromboembolic complications in women using CHCs may be significantly higher in the presence of additional risk factors, especially multiple ones (see Table 1).

The use of Josegood® is contraindicated in women with multiple risk factors that may increase the risk of developing venous thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the increased risk may be greater than the sum of the risks associated with each individual factor, so the overall risk of developing VTE should be taken into account. If the benefit/risk ratio is unfavorable, CHCs should not be prescribed (see section "Contraindications").

Table 1.

Risk factors for developing VTE

There is no consensus on the possible impact of varicose veins and superficial thrombophlebitis on the development and progression of venous thrombosis.

Attention should be paid to the increased risk of thromboembolism during pregnancy, especially during the 6 weeks after delivery (for information on pregnancy or breastfeeding, see section "Use during pregnancy or breastfeeding").

Symptoms of VTE (deep vein thrombosis and pulmonary embolism)

Women should be advised to contact their doctor immediately if they experience the following symptoms and to inform them that they are using CHCs.

Symptoms of PE may include: sudden unexplained shortness of breath or rapid breathing; sudden cough, possibly with blood; sudden chest pain; fainting or dizziness; and a fast or irregular heartbeat.

Some of these symptoms (e.g., shortness of breath, cough) are nonspecific or may be misinterpreted as more common or less severe conditions (e.g., respiratory tract infections).

Other manifestations of vascular occlusion may include sudden pain, swelling, acute abdomen, and slight blueness of the limb.

In the case of occlusion of the vessels of the eye, the initial symptom may be blurred vision, which is not accompanied by pain, and which can progress to loss of vision. Sometimes the loss of vision develops almost instantly.

Risk of developing arterial thromboembolism (ATE)

Epidemiological studies have shown that the use of any CHC is associated with an increased risk of arterial thromboembolism (myocardial infarction) or cerebrovascular events (transient ischemic attack, stroke). Arterial thromboembolic events can be fatal.

Risk factors for developing ATE

When using CHCs, the risk of arterial thromboembolic complications or cerebrovascular events is increased in women with risk factors (see Table 2). The use of the drug Josegood® is contraindicated if women have one serious or multiple risk factors for ATE that may increase the risk of developing arterial thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the increased risk may be greater than the sum of the risks associated with each individual factor, so the overall risk should be taken into account. If the benefit/risk ratio is unfavorable, CHCs should not be prescribed (see section "Contraindications").

Table 2.

Risk factors for developing ATE

Symptoms of ATE

Women should be advised to contact their doctor immediately if they experience the symptoms listed below and to inform them that they are using CHCs.

Symptoms of a cerebrovascular accident may include: sudden numbness of the face, weakness or numbness of the limbs, especially on one side; sudden trouble walking, dizziness, loss of balance or coordination; sudden confusion, trouble speaking or understanding; sudden loss of vision in one or both eyes; sudden, severe or prolonged headache with no known cause; loss of consciousness or fainting with or without seizures.

The transient nature of the symptoms may indicate a transient ischemic attack (TIA).

Symptoms of a myocardial infarction may include: pain, discomfort, a feeling of squeezing or heaviness in the chest, arm or below the breastbone; discomfort radiating to the back, jaw, throat, arm, stomach; a feeling of fullness in the stomach, indigestion or shortness of breath; increased sweating, nausea, vomiting or dizziness; extreme weakness, anxiety or shortness of breath; fast or irregular heartbeat.

Tumors

The results of some epidemiological studies indicate an additional increase in the risk of developing cervical cancer with long-term use of COCs (> 5 years), but this statement remains controversial, since it is not yet clear to what extent the results of the studies take into account concomitant risk factors, such as sexual behavior, and other factors, such as human papillomavirus infection.

Malignant neoplasms

Breast cancer

Drospirenone; ethinylestradiol is contraindicated in women with current or past breast cancer, as breast cancer may be hormone-sensitive (see Contraindications).

In isolated cases, benign and even more rarely malignant liver tumors have been observed in women using COCs, which in some cases led to life-threatening intra-abdominal bleeding. In case of complaints of severe epigastric pain, liver enlargement or signs of intra-abdominal bleeding, the possibility of a liver tumor should be considered in the differential diagnosis when using COCs.

High-dose COCs (50 mcg ethinylestradiol) reduce the risk of endometrial and ovarian cancer. It remains to be confirmed whether these findings can also be extended to low-dose COCs.

Other states

The progestin component of Josegood® is an aldosterone antagonist with potassium-sparing properties. In most cases of use, an increase in potassium levels is not expected. In clinical studies, in some patients with mild to moderate renal insufficiency and concomitant use of potassium-sparing drugs, serum potassium levels increased slightly, but not significantly, during the use of drospirenone. Therefore, monitoring of potassium levels is recommended during the first treatment cycle in patients with renal insufficiency. These patients are also recommended to maintain serum potassium levels not above the upper limit of normal before starting the drug, especially when taking potassium-sparing drugs (see section “Interaction with other medicinal products and other forms of interaction”).

Women with hypertriglyceridemia or a family history of this disorder are at risk of developing pancreatitis when using COCs.

Although a slight increase in blood pressure has been reported in many women taking COCs, clinically significant increases in blood pressure have been observed in isolated cases. Immediate discontinuation of COCs is only necessary in these isolated cases. In the case of persistent hypertension or failure to control blood pressure with antihypertensive drugs, women taking COCs should discontinue their use. If appropriate, COC use can be resumed after achieving normotensive status with antihypertensive therapy.

The following conditions have been reported to occur or worsen during pregnancy and COC use, but the relationship to estrogen/progestin use is not conclusive: jaundice and/or pruritus associated with cholestasis, gallstone formation, porphyria, systemic lupus erythematosus, hemolytic uremic syndrome, Sydenham's chorea, herpes gestationis, hearing loss associated with otosclerosis.

In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

Acute or chronic liver function disorders may require discontinuation of COC use until liver function tests return to normal and a causal relationship to COC use has been ruled out.

If cholestatic jaundice and/or itching associated with cholestasis recurs, which previously occurred during pregnancy or previous use of sex hormones, COC use should be discontinued.

Although COCs may affect peripheral insulin resistance and glucose tolerance, there is no evidence to suggest that diabetic women taking low-dose COCs (ethinylestradiol) should be given special medical attention. However, diabetic women should be closely monitored during COC use, especially at the beginning of treatment.

Cases of exacerbation of epilepsy, Crohn's disease and ulcerative colitis have also been observed during the use of COCs.

Depressed mood and depression are well-known side effects that can occur with hormonal contraceptives (see section 4.8). Depression can be a serious condition and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to seek medical advice if they experience mood changes or symptoms of depression, including shortly after starting treatment.

Sometimes chloasma may occur, o