Yaz^® Plus (Tablet kit) Instructions for Use

Marketing Authorization Holder

Bayer, AG (Germany)

Manufactured By

Bayer Weimar, GmbH & Co. KG (Germany)

Contact Information

Bayer AG (Germany)

ATC Code

G03AA12 (Drospirenone and Ethinylestradiol)

Active Substances

Ethinylestradiol (Rec.INN registered by WHO)

Drospirenone (Rec.INN registered by WHO)

Levomefolate calcium (USAN adopted for use in the USA)

Dosage Form

Yaz® Plus

Kit of film-coated tablets, 3 mg+0.02 mg+0.451 mg and 0.451 mg: 28 or 84 pcs. in a set with a block of stickers for creating a dosing calendar

Dosage Form, Packaging, and Composition

Kit of film-coated tablets (tablets with a combination of active substances and auxiliary vitamin tablets).

Film-coated tablets (with a combination of active substances) are pink, round, biconvex, with an embossing “Z+” in a regular hexagon on one side; (24 pcs. in a blister).

Excipients: lactose monohydrate – 45.329 mg, microcrystalline cellulose – 24.8 mg, croscarmellose sodium – 3.2 mg, hypromellose (5 cP) – 1.6 mg, magnesium stearate – 1.6 mg.

Coating composition pink lacquer – 2 mg or (alternatively): hypromellose (5 cP) – 1.0112 mg, macrogol 6000 – 0.2024 mg, talc – 0.2024 mg, titanium dioxide – 0.558 mg, iron oxide red dye – 0.026 mg.

Film-coated tablets (auxiliary vitamin) are light orange, round, biconvex, with an embossing “M+” in a regular hexagon on one side; (4 pcs. in a blister).

Excipients: lactose monohydrate – 48.349 mg, microcrystalline cellulose – 24.8 mg, croscarmellose sodium – 3.2 mg, hypromellose (5 cP) – 1.6 mg, magnesium stearate – 1.6 mg.

Coating composition light orange lacquer – 2 mg or (alternatively): hypromellose (5 cP) – 1.0112 mg, macrogol 6000 – 0.2024 mg, talc – 0.2024 mg, titanium dioxide – 0.5723 mg, iron oxide yellow dye – 0.0089 mg, iron oxide red dye – 0.0028 mg.

28 pcs. (kit: 24 tablets with a combination of active substances and 4 auxiliary vitamin tablets) – contour cell packaging (blisters) (1) – dispenser packs (1) with an inserted block of self-adhesive stickers for creating a dosing calendar – film^×.
28 pcs. (kit: 24 tablets with a combination of active substances and 4 auxiliary vitamin tablets) – contour cell packaging (blisters) (1) – dispenser packs (3) with an inserted block of self-adhesive stickers for creating a dosing calendar – film^×.

^× A packaging sticker is applied to the transparent film.

Clinical-Pharmacological Group

Contraceptive combined drug (estrogen + progestogen + calcium levomefolate)

Pharmacotherapeutic Group

Combined contraceptive agent (estrogen + gestagen + calcium levomefolate)

Pharmacological Action

Yaz^® Plus is a low-dose monophasic combined estrogen-progestin contraceptive drug, consisting of tablets containing hormones and calcium levomefolate, and auxiliary tablets containing only calcium levomefolate.

The contraceptive effect of combined oral contraceptive drugs (COCs) is based on the interaction of various factors, the most important of which are suppression of ovulation, increased viscosity of cervical secretion, and changes in the endometrium.

In women taking COCs, the menstrual cycle becomes more regular, the painfulness, intensity and duration of menstrual-like bleeding decrease, resulting in a reduced risk of developing iron deficiency anemia. There is also evidence of a reduced risk of developing endometrial and ovarian cancer.

Drospirenone, which is part of the drug Yaz^® Plus, has antimineralocorticoid activity and helps prevent hormone-dependent fluid retention, which may manifest as a decrease in body weight and a reduced likelihood of peripheral edema, ensuring good tolerability of the drug. Drospirenone has a positive effect on premenstrual syndrome. In combination with ethinylestradiol, Drospirenone demonstrates a favorable effect on the lipid profile, characterized by an increase in HDL. Drospirenone also has antiandrogenic activity and helps reduce acne, oily skin and hair (seborrhea). These features of drospirenone should be considered when choosing a contraceptive for women with hormone-dependent fluid retention, as well as for women with acne and seborrhea. Drospirenone does not possess androgenic, estrogenic, glucocorticoid or antiglucocorticoid activity. All this, combined with antimineralocorticoid and antiandrogenic action, gives drospirenone a biochemical and pharmacological profile similar to natural progesterone. When used correctly, the Pearl index (an indicator reflecting the number of pregnancies in 100 women using the contraceptive for one year) is less than 1. If tablets are missed or the drug is used incorrectly, the Pearl index may increase.

The acid form of calcium levomefolate is structurally identical to the natural L-5-methyltetrahydrofolate (L-5-methyl-THF), the main folate form found in food. The average concentration of L-5-methyltetrahydrofolate in the blood plasma of people not using food fortified with folic acid is about 15 nmol/L.

Levomefolate, unlike folic acid, is a biologically active form of folate, which allows it to be absorbed better than folic acid. Folate deficiency correlates with an increased risk of fetal neural tube defects. Taking calcium levomefolate is recommended for women before pregnancy to meet the increased need for folates in the early stages of pregnancy. It may take several weeks to achieve optimal folate levels.

Pharmacokinetics

Drospirenone

Absorption

After oral administration, Drospirenone is rapidly and almost completely absorbed. After a single oral dose, the C_max of drospirenone in plasma, equal to 38 ng/ml, is reached after 1-2 hours. Food intake does not affect bioavailability, which ranges from 76% to 85%.

Distribution

After oral administration, a biphasic decrease in the concentration of drospirenone in plasma is observed with T_1/2 of 1.6±0.7 hours and 27±7.5 hours, respectively. Drospirenone binds to serum albumin and does not bind to sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG). Only 3-5% of the total serum concentration is present as free hormone. Ethinylestradiol-induced increase in SHBG does not affect the protein binding of drospirenone. The mean apparent V_d is 3.7±1.2 L/kg.

Steady-state concentration. During the first course of drug use, the C_ss of drospirenone in plasma of about 70 ng/ml is reached after 8 days from the start of drug use. An increase in the plasma concentration of drospirenone by approximately 2-3 times (due to accumulation) was noted, which was due to the ratio of T_1/2 in the terminal phase and the dosing interval. A further increase in the plasma concentration of drospirenone is noted after 1-6 courses of drug use, after which no increase in concentration is observed.

Metabolism

After oral administration, Drospirenone is intensively metabolized. Most metabolites in plasma are represented by acid forms of drospirenone. Drospirenone is also a substrate for oxidative metabolism catalyzed by the CYP3A4 isoenzyme.

Excretion

The metabolic clearance rate of drospirenone in plasma is 1.5±0.2 ml/min/kg. Drospirenone is excreted unchanged only in trace amounts. Metabolites of drospirenone are excreted through the gastrointestinal tract and kidneys in a ratio of approximately 1.2:1.4. T_1/2 of metabolites is about 40 hours.

Pharmacokinetics in special patient groups

Renal impairment. Studies have shown that the plasma concentration of drospirenone in women with mild renal impairment (CrCl 50-80 ml/min) at steady state and in women with normal renal function (CrCl greater than 80 ml/min) are comparable. However, in women with moderate renal impairment (CrCl 30-50 ml/min), the average plasma concentration of drospirenone was 37% higher than in patients with normal renal function. No change in plasma potassium concentration was noted with the use of drospirenone. The pharmacokinetics of drospirenone has not been studied in patients with severe renal impairment.

Hepatic impairment. In women with moderate hepatic impairment (Child-Pugh class B), the AUC is comparable to that in healthy women with similar C_max values in the absorption and distribution phases. The T_1/2 of drospirenone in patients with moderate hepatic impairment was 1.8 times higher than in healthy volunteers with normal liver function.

In patients with moderate hepatic impairment, a decrease in the clearance of drospirenone of about 50% was noted compared to women with normal liver function, while no differences in plasma potassium concentration were noted in the studied groups. No changes in potassium concentration were noted even in the case of a combination of factors predisposing to its increase (concomitant diabetes mellitus or treatment with spironolactone). The pharmacokinetics of drospirenone has not been studied in patients with severe hepatic impairment.

Ethnicity. No effect of ethnicity (study conducted on cohorts of Caucasian women and Japanese women) on the pharmacokinetic parameters of drospirenone and ethinylestradiol was established.

Ethinylestradiol

Absorption

After oral administration, Ethinylestradiol is rapidly and completely absorbed. C_max is about 33 pg/ml, reached within 1-2 hours after a single oral dose. Absolute bioavailability as a result of presystemic conjugation and first-pass metabolism is approximately 60%. Concomitant food intake reduces the bioavailability of ethinylestradiol in about 25% of the subjects, while no such changes were noted in other subjects.

Distribution

The concentration of ethinylestradiol in plasma decreases biphasically, the T_1/2 of ethinylestradiol in the second phase is about 24 hours. Ethinylestradiol is non-specifically but strongly bound to plasma albumin (about 98.5%) and induces an increase in plasma SHBG concentration. The estimated V_d is about 5 L/kg.

Steady-state concentration. C_ss is reached in the second half of the drug intake cycle, the plasma concentration of ethinylestradiol increases by approximately 1.4-2.1 times.

Metabolism

Ethinylestradiol undergoes significant primary metabolism in the intestine and liver. Ethinylestradiol and its oxidative metabolites are primarily conjugated with glucuronides or sulfate. The metabolic clearance rate of ethinylestradiol is about 5 ml/min/kg.

Excretion

Ethinylestradiol is practically not excreted unchanged. Metabolites of ethinylestradiol are excreted by the kidneys and through the intestines in a ratio of 4:6. T_1/2 of metabolites is approximately 24 hours.

Calcium levomefolate

Absorption

After oral administration, calcium levomefolate is rapidly absorbed and incorporated into the body’s folate pool. After a single oral dose of 451 mcg of calcium levomefolate, after 0.5-1.5 hours, C_max becomes 50 nmol/L higher than the baseline concentration.

Distribution

The pharmacokinetics of folates is biphasic: a folate pool with fast and slow metabolism is determined. The pool with fast metabolism probably represents newly arrived folates in the body, which is consistent with the T_1/2 of calcium levomefolate, which is about 4-5 hours after its single oral administration at a dose of 451 mcg. The pool with slow metabolism reflects the conversion of folate polyglutamate, the T_1/2 of which is about 100 days. Exogenous folates and folates undergoing enterohepatic circulation maintain a constant concentration of L-5-methyl-THF in the body.

L-5-methyl-THF represents the main form of folates in the body, in which they are delivered to peripheral tissues to participate in cellular folate metabolism.

Steady-state concentration. The C_ss of L-5-methyl-THF in plasma after oral administration of 451 mcg of calcium levomefolate is reached after 8-16 weeks and depends on its baseline concentration. In erythrocytes, C_ss is reached at a later date due to the lifespan of erythrocytes, which is about 120 days.

Metabolism

L-5-methyl-THF represents the main folate transport form in plasma. When comparing 451 mcg of calcium levomefolate and 400 mcg of folic acid, similar mechanisms of metabolism were established for other significant folates. Folate coenzymes are involved in 3 main coupled cycles of metabolism in the cytoplasm of cells. These cycles are necessary for the synthesis of thymidine and purines, precursors of DNA and RNA acids, as well as for the synthesis of methionine from homocysteine and the conversion of serine to glycine.

Excretion

L-5-methyl-THF is excreted by the kidneys unchanged and as metabolites, as well as through the gastrointestinal tract.

Indications

• Contraception intended primarily for women with symptoms of hormone-dependent fluid retention in the body;
• Contraception and treatment of acne vulgaris of moderate severity;
• Contraception in women with folate deficiency;
• Contraception and treatment of severe premenstrual syndrome.

ICD codes

Dosage Regimen

When and how to take the tablets

The tablets should be taken orally in the order indicated on the package, every day at the same time, without chewing, with a small amount of water. Take 1 tab./day continuously for 28 days. Taking tablets from the next package starts immediately after finishing the previous package.

Withdrawal bleeding usually begins on the 2nd-3rd day after starting to take the hormone-free tablets and may not have ended before starting to take tablets from the next package.

Taking tablets from the first package of the drug Yaz^® Plus

If no hormonal contraceptives were taken in the previous month

The drug Yaz^® Plus should be started on the 1st day of the menstrual cycle (i.e., on the 1st day of menstrual bleeding). On this day, one pink (hormone-containing) tablet marked with the corresponding day of the week should be taken. Then the tablets should be taken in order. It is permissible to start taking the drug on the 2nd-5th day of the menstrual cycle, but in this case, during the first 7 days of taking the pink tablets, it is necessary to additionally use a barrier method of contraception (for example, a condom).

When switching from other combined contraceptive drugs (COC, contraceptive vaginal ring or contraceptive patch)

It is preferable to start taking the drug Yaz^® Plus on the day after taking the last active hormone-containing tablet from the package of the previous COC, but in no case later than the next day after the usual 7-day break (for drugs containing 21 tablets) or after taking the last hormone-free tablet (for drugs containing 28 tablets per package). Taking the drug Yaz^® Plus should be started after the usual break in taking active tablets when switching from contraceptive drugs with an extended regimen of use. Taking the drug Yaz^® Plus should be started on the day of removal of the vaginal ring or patch, but no later than the day when a new ring should be inserted or a new patch applied.

When switching from contraceptives containing only progestogens (“mini-pills”, injectable forms, implant), or from an intrauterine therapeutic system releasing progestogen

You can switch from “mini-pills” to the drug Yaz^® Plus on any day (without a break), from an implant or intrauterine contraceptive with progestogen – on the day of their removal, from an injectable contraceptive – on the day when the next injection should be made. In all cases, during the first 7 days of taking the drug Yaz^® Plus, it is necessary to additionally use a barrier method of contraception (for example, a condom).

After an abortion (including spontaneous) in the first trimester of pregnancy

Taking the drug can be started immediately. If this condition is met, no additional contraceptive measures are required.

After childbirth (in the absence of breastfeeding) or abortion (including spontaneous) in the second trimester of pregnancy

It is recommended to start taking the drug on the 21st-28th day after childbirth or abortion (including spontaneous) in the second trimester of pregnancy. If the drug is started later, it is necessary to additionally use a barrier method of contraception during the first 7 days of taking the tablets. However, if sexual intercourse has occurred, pregnancy should be excluded before starting the drug Yaz^® Plus.

The dispenser pack contains a blister with 24 pink tablets and 4 auxiliary (light orange) tablets (bottom row). The package also contains a block of stickers, consisting of 7 self-adhesive strips with the names of the days of the week marked on them, necessary for creating a dosing calendar. It is necessary to select the strip where the first indicated day of the week is the one on which the tablet intake begins. For example, if the start of tablet intake falls on a Wednesday, the strip that begins with “Wed.” should be used. (see Fig. 1).

Fig. 1

The strip is affixed along the top part of the package so that the designation of the first day is above the tablet pointed to by the arrow labeled “Start” (Fig. 2).

Fig. 2

This will make it clear on which day of the week each tablet should be taken (Fig. 3).

Fig. 3

Taking Missed Tablets

Missing the auxiliary light-orange tablets can be ignored. However, the missed tablets should be discarded to avoid accidentally extending the period of taking the auxiliary tablets. The following recommendations apply only to missing active pink tablets (tablets 1-24 in the pack).

If the delay in taking a pink tablet is less than 24 hours, contraceptive protection is not reduced. The woman should take the missed tablet as soon as possible, and take the next tablets at the usual time.

If the delay in taking a pink tablet is more than 24 hours, contraceptive protection may be reduced. The more tablets are missed and the closer the missed tablets are to the phase of taking light-orange (auxiliary) tablets, the higher the risk of pregnancy.

It must be remembered that

• Tablet intake should never be interrupted for more than 7 days (note that the recommended interval for taking light-orange (auxiliary) tablets is 4 days);
• 7 days of continuous intake of pink tablets are required to achieve adequate suppression of the hypothalamic-pituitary-ovarian system.

Accordingly, if the delay in taking pink (active) tablets is more than 24 hours, the following should be done

Days 1 to 7

The woman should take the last missed tablet as soon as she remembers, even if this means taking 2 tablets at the same time. The next tablets should be taken at the usual time. Additionally, a barrier method of contraception (e.g., condom) must be used for the next 7 days. If sexual intercourse occurred within the 7 days before missing the tablet, the possibility of pregnancy should be considered.

Days 8 to 14

The woman should take the last missed tablet as soon as she remembers, even if this means taking 2 tablets at the same time. She should continue taking the next tablets at the usual time.

Provided that the tablet regimen was followed correctly for the 7 days preceding the first missed tablet, there is no need to use additional contraceptive measures. Otherwise, and also if two or more tablets were missed, additional barrier contraceptive methods (e.g., condom) must be used for the next 7 days.

Days 15 to 24

The risk of reduced contraceptive reliability is inevitable due to the approaching phase of taking light-orange (auxiliary) tablets. In this case, the following algorithms should be followed

• If all tablets were taken correctly during the 7 days preceding the first missed tablet, there is no need to use additional contraceptive methods. When taking the missed tablets, follow points 1 or 2;
• If tablets were taken incorrectly during the 7 days preceding the first missed tablet, then a barrier method of contraception (e.g., condom) must be used additionally for the next 7 days, and in this case, follow point 1 for taking the missed tablets.

1. Take the missed tablet as soon as possible, as soon as the woman remembers (even if this means taking 2 tablets at the same time). Take the next tablets at the usual time until the pink tablets in the pack are finished. The four light-orange (auxiliary) tablets should be discarded and intake of pink tablets from a new pack should be started immediately. Until the pink tablets from the second pack are finished, withdrawal bleeding is unlikely, however, spotting and/or breakthrough bleeding may occur.
2. Discontinue taking pink tablets from the current pack, then take a break for 4 days or less (including the days of missed tablets), after which start taking the drug from a new pack.

If a woman missed taking pink (active) tablets and withdrawal bleeding did not occur during the intake of light-orange (auxiliary) tablets, the absence of pregnancy must be confirmed.

For convenience, this information is presented on the package in the following scheme

It is allowed to take no more than 2 tablets in one day.

Recommendations for Gastrointestinal Disorders

In severe gastrointestinal disorders, the absorption of the drug may be incomplete, so additional contraceptive measures should be taken.

If vomiting or diarrhea occurs within 3-4 hours after taking a pink tablet, the recommendations for missed tablets should be followed. If the woman does not want to change her usual regimen and shift the start of menstruation to another day of the week, an additional pink tablet should be taken from another pack.

Discontinuation of Jess^® Plus

Intake of Jess^® Plus can be discontinued at any time. If the woman is not planning a pregnancy, other methods of contraception should be arranged. If pregnancy is planned, simply discontinue taking Jess^® Plus, wait for a natural menstrual bleeding, and then attempt to become pregnant. This will help calculate the pregnancy term and delivery date more accurately.

Delaying the Onset of Menstrual-like Bleeding

To delay the onset of withdrawal bleeding, skip taking the 4 light-orange (auxiliary) tablets from the current pack and start taking pink tablets from the next pack of Jess^® Plus. If all 24 pink tablets from the second pack have been taken, then the 4 light-orange tablets should also be taken in this case. Only after this can tablet intake from a new pack be started. Thus, the cycle can be extended, as desired, for any period, up until all pink tablets from the second pack have been taken. If the woman wants the menstrual-like bleeding to start earlier, she should discontinue taking the pink tablets from the second pack, discard it, and take a break from all tablets for no more than 4 days, then start taking tablets from a new pack. In this case, menstrual-like bleeding will start approximately 2-3 days after taking the last pink tablet from the second pack. During the intake of Jess^® Plus from the second pack, spotting and/or breakthrough bleeding may occur on the days of taking pink tablets.

Changing the Day of Onset of Menstrual-like Bleeding

If the drug tablets are taken according to the recommendations, menstrual-like bleeding will occur approximately on the same day every 4 weeks. If a woman wants to change the day of onset of menstrual-like bleeding, she should stop taking the light-orange tablets for as many days as she wants to shift the onset of menstrual-like bleeding. For example, if the cycle usually starts on Friday, and in the future the woman wants it to start on Tuesday (3 days earlier), tablet intake from the next pack should be started 3 days earlier than usual, i.e., do not use the last 3 light-orange tablets from the current pack and start taking tablets from the next pack. The fewer light-orange tablets a woman takes, the higher the likelihood that menstrual-like bleeding will not occur. During the intake of Jess^® Plus from the next pack, spotting and/or breakthrough bleeding may occur.

Use in Specific Patient Groups

Adolescent girls. Jess^® Plus is indicated only after menarche. Available data do not suggest dose adjustment in this patient group.

Elderly patients. Jess^® Plus is not used after menopause.

Patients with impaired liver function. The drug is contraindicated in women with severe liver function disorders (see also sections “Contraindications” and “Pharmacokinetics”).

Patients with impaired renal function. The drug is contraindicated in women with severe renal function disorders and in acute renal failure (see also sections “Contraindications” and “Pharmacokinetics”).

Adverse Reactions

The most common adverse reactions reported in association with the use of the drug Jess^® are as follows: nausea, breast pain, irregular uterine bleeding, genital bleeding of unspecified origin (in more than 3% of women using the drug for the indications “Contraception” and “Contraception and treatment of moderate acne vulgaris”); nausea, breast pain, irregular uterine bleeding (in more than 10% of women using the drug for the indication “Contraception and treatment of severe premenstrual syndrome (PMS)”).

Serious adverse reactions are ATE and VTE.

The table below shows the frequency of adverse reactions reported during clinical trials of the drugs Jess^® and Jess^® Plus for the indication “Contraception”, as well as for the indications “Contraception and treatment of moderate acne vulgaris” (n=3565) and “Contraception and treatment of severe premenstrual syndrome (PMS)” (n=289) for the drug Jess^®. Within each frequency group, adverse reactions are presented in order of decreasing severity. Definition of adverse reaction frequency categories: common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), and rare (≥1/10,000 and <1/1000). For additional adverse reactions identified only during post-marketing surveillance and for which frequency estimation was not possible, "frequency unknown" is indicated.

Adverse events were classified using the MedDRA dictionary. Different MedDRA terms reflecting the same symptom were grouped together and presented as a single adverse reaction, to avoid diluting or blurring the true effect.

* Approximate frequency based on epidemiological studies covering the COC group. The frequency bordered on very rare.

“Venous or arterial thromboembolism” includes the following nosological units: peripheral deep vein occlusion, thrombosis and embolism/occlusion of pulmonary vessels, thrombosis, embolism and infarction/myocardial infarction/cerebral infarction and hemorrhagic stroke.

¹Frequency in studies evaluating PMS was very common >10/100.

²Frequency in studies evaluating PMS was common ≥1/100.

For venous and arterial thromboembolism, migraine see also sections “Contraindications” and “Special warnings and precautions”.

Additional Information

Listed below are adverse reactions with very rare frequency or with delayed symptoms that are believed to be possibly associated with the use of drugs from the COC group (see also sections “Contraindications” and “Special warnings and precautions”).

Neoplasms

• In women using COCs, the frequency of detecting breast cancer is very slightly increased. Since breast cancer is rare in women under 40 years of age, the increase in frequency in women using COCs is insignificant relative to the overall risk of breast cancer. A causal relationship with COC use is unknown;
• Liver tumors (benign and malignant).

Other conditions

• Erythema nodosum;
• Hypertriglyceridemia (increased risk of pancreatitis during COC use);
• Increased blood pressure;
• Conditions that develop or worsen during COC use, but their connection is not proven (jaundice and/or pruritus associated with cholestasis; gallstone formation; epilepsy; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; Sydenham’s chorea; herpes gestationis; hearing loss associated with otosclerosis);
• In women with hereditary angioedema, estrogen intake may cause or worsen its symptoms;
• Liver function disorders;
• Changes in glucose tolerance or effect on insulin resistance;
• Crohn’s disease, ulcerative colitis;
• Chloasma;
• Hypersensitivity (including symptoms such as rash, urticaria).

Interaction

Interaction of oral contraceptives with other medicinal products (enzyme inducers) may lead to breakthrough bleeding and/or reduced contraceptive efficacy (see section “Drug interactions”).

Contraindications

Jess^® Plus is contraindicated in the presence of any of the conditions/diseases/risk factors listed below. If any of these conditions/diseases develop for the first time during use, the drug should be discontinued immediately.

• Thrombosis (venous and arterial) and thromboembolism (including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke), cerebrovascular disorders – currently or in history;
• Conditions preceding thrombosis (including transient ischemic attacks, angina pectoris) currently or in history;
• Identified acquired or hereditary predisposition to venous or arterial thrombosis, including activated protein C resistance, antithrombin III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
• Presence of high risk of venous or arterial thrombosis (see section “Special warnings and precautions”);
• Migraine with focal neurological symptoms currently or in history;
• Pancreatitis with severe hypertriglyceridemia currently or in history;
• Diabetes mellitus with vascular complications;
• Hepatic failure and severe chronic liver diseases (until liver tests normalize);
• Severe and/or acute renal failure;
• Liver tumors (benign or malignant) currently or in history;
• Identified hormone-dependent malignant neoplasms (including of the genital organs or breasts) or suspicion thereof;
• Vaginal bleeding of unknown origin;
• Concomitant use with direct-acting antiviral drugs (DAA) containing ombitasvir, paritaprevir, dasabuvir or a combination of these substances (see section “Drug interactions”);
• Pregnancy or suspected pregnancy;
• Period of breastfeeding;
• Rare hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption (because the drug contains lactose);
• Hypersensitivity or intolerance to drospirenone, ethinylestradiol, calcium levomefolate or any of the excipients of Jess^® Plus.

With caution

The potential risk and expected benefit of using Jess^® Plus should be evaluated in each individual case in the presence of the following diseases/conditions and risk factors

• Risk factors for thrombosis and thromboembolism: smoking, obesity, dyslipoproteinemia, controlled arterial hypertension, migraine without focal neurological symptoms, uncomplicated valvular heart defects, hereditary predisposition to thrombosis (thrombosis, myocardial infarction or cerebrovascular accident at the age of less than 50 years in any first-degree relative);
• Other diseases in which peripheral circulatory disorders may be noted: diabetes mellitus without vascular complications, systemic lupus erythematosus, hemolytic-uremic syndrome, Crohn’s disease and ulcerative colitis, sickle cell anemia, superficial phlebitis;
• Hereditary angioedema;
• Hypertriglyceridemia;
• History of mild to moderate liver diseases with normal liver function tests;
• Diseases that first appeared or worsened during pregnancy or while taking sex hormones previously (e.g., cholestasis-related jaundice and/or pruritus, cholelithiasis, otosclerosis with hearing impairment, porphyria, herpes gestations, Sydenham’s chorea);
• Postpartum period.

Use in Pregnancy and Lactation

Pregnancy

The drug is contraindicated during pregnancy. If pregnancy is detected while using Jess^® Plus, the drug should be discontinued immediately. Available data on the use of Jess^® Plus during pregnancy are limited and do not allow any conclusions to be drawn about the negative impact of the drug on pregnancy, the health of the fetus and the newborn. At the same time, extensive epidemiological studies have not revealed an increased risk of developmental defects in children born to women who took COCs before pregnancy, or a teratogenic effect in cases of inadvertent COC use in early pregnancy. No specific epidemiological studies have been conducted regarding Jess^® Plus.

Breastfeeding period

The drug is contraindicated during breastfeeding. Taking the drug may reduce the amount of breast milk and change its composition, therefore the use of Jess^® Plus is contraindicated until breastfeeding is discontinued. A small amount of sex hormones and/or their metabolites may pass into breast milk and affect the child’s health.

Use in Hepatic Impairment

The drug is contraindicated for use in women with hepatic insufficiency and severe liver diseases (until liver tests normalize); liver tumors (benign or malignant) currently or in history.

With caution: history of mild to moderate liver diseases with normal liver function tests.

Use in Renal Impairment

The drug is contraindicated for use in women with severe renal impairment and acute renal failure.

Pediatric Use

Jess^® Plus is indicated only after menarche. Available data do not suggest a dose adjustment in this patient group.

Geriatric Use

Jess^® Plus is not used after menopause.

Special Precautions

If any of the conditions, diseases and risk factors listed below are currently present, the potential risk and expected benefit of using Jess^® Plus should be carefully weighed in each individual case and discussed with the woman before she decides to start taking this drug.

Cardiovascular system disorders

Results of epidemiological studies indicate a relationship between the use of COCs and an increased incidence of venous and arterial thrombosis and thromboembolism (such as deep vein thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular disorders) when taking COCs. These diseases are rare.

The risk of developing venous thromboembolism (VTE) is highest in the first year of taking COCs. An increased risk is present after initial use of a COC or resumption of use of the same or a different COC (after a drug-free interval of 4 weeks or more). Data from a large prospective study involving 3 patient groups show that this increased risk is present predominantly during the first 3 months.

The overall risk of VTE in patients taking low-dose COCs (<50 mcg ethinyl estradiol) is 2-3 times higher than in non-pregnant patients who do not take COCs, nevertheless, this risk remains lower compared to the risk of VTE during pregnancy and childbirth.

VTE can be life-threatening or fatal (in 1-2% of cases).

VTE, manifesting as deep vein thrombosis or pulmonary embolism, can occur with the use of any COCs.

Very rarely, thrombosis of other blood vessels, such as hepatic, mesenteric, renal, cerebral veins and arteries or retinal vessels, occurs with the use of COCs.

Symptoms of deep vein thrombosis (DVT): unilateral swelling of the lower limb or along a vein in the lower limb, pain or discomfort in the lower limb only in an upright position or when walking, local increase in temperature in the affected lower limb, redness or discoloration of the skin on the lower limb.

Symptoms of pulmonary embolism (PE): difficult or rapid breathing; sudden cough, including with hemoptysis; sharp pain in the chest, which may intensify with a deep breath; feeling of anxiety; severe dizziness; rapid or irregular heartbeat. Some of these symptoms (e.g., shortness of breath, cough) are nonspecific and may be misinterpreted as signs of other more common and less severe conditions/diseases (e.g., respiratory tract infection).

ATE can lead to stroke, vascular occlusion or myocardial infarction.

Symptoms of stroke: sudden weakness or loss of sensation in the face, limbs, especially on one side of the body, sudden confusion, problems with speech and understanding; sudden unilateral or bilateral loss of vision; sudden gait disturbance, dizziness, loss of balance or coordination; sudden, severe or prolonged headache for no apparent reason; loss of consciousness or fainting with or without a seizure.

Other signs of vascular occlusion: sudden pain, swelling and slight bluish discoloration of the limbs, “acute abdomen” symptom complex.

Symptoms of myocardial infarction: pain, discomfort, pressure, heaviness, feeling of squeezing or fullness in the chest or behind the breastbone with radiation to the back, jaw, left upper limb, epigastric region; cold sweat, nausea, vomiting or dizziness, severe weakness, anxiety or shortness of breath; rapid or irregular heartbeat.

ATE can be life-threatening or fatal.

In women with a combination of several risk factors or a high severity of one of them (for example, complicated heart valve diseases, uncontrolled arterial hypertension, major surgical interventions with prolonged immobilization and others), the possibility of their mutual enhancement should be considered. In such cases, the total value of the existing risk factors increases. In this case, taking Jess^® Plus is contraindicated.

The risk of developing thrombosis (venous and/or arterial) and thromboembolism or cerebrovascular disorders increases

• With age;
• In smokers (with an increase in the number of cigarettes or increasing age, the risk increases, especially in women over 35 years old);

In the presence of

• Obesity (BMI over 30 kg/m²);
• Indications in the family history (e.g., venous or arterial thromboembolism ever in close relatives or parents under the age of 50). In case of a hereditary or acquired predisposition, a woman should be examined by an appropriate specialist to decide on the possibility of taking Jess^® Plus;
• Prolonged immobilization, major surgery, any surgery on the lower limbs or extensive trauma. In these situations, it is necessary to stop using Jess^® Plus (in the case of planned surgery, at least 4 weeks before it) and not resume taking it for 2 weeks after the end of immobilization. Temporary immobilization (e.g., air travel lasting more than 4 hours) may also be a risk factor for the development of venous thromboembolism, especially in the presence of other risk factors;
• Dyslipoproteinemia;
• Arterial hypertension;
• Migraine;
• Heart valve diseases;
• Atrial fibrillation.

The use of any combined hormonal contraceptives increases the risk of developing VTE. The use of drugs containing levonorgestrel, norgestimate or norethisterone carries the lowest risk of developing VTE. The use of other drugs, such as Jess^® Plus, may lead to a twofold increase in risk. The decision to use a COC with a higher risk of VTE can only be made after consulting the patient, ensuring that she fully understands the risk of VTE associated with the use of Jess^® Plus, the effect of the drug on her existing risk factors, and that the risk of VTE is highest during the first year of use. According to some data, an increased risk is noted when resuming COC use after a break of 4 weeks or more.

Approximately 9-12 out of 10,000 women taking COCs containing Drospirenone may develop VTE within a year, whereas for COCs containing levonorgestrel, this figure was about 6 out of 10,000 women.

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 taken into account.

Peripheral circulatory disorders may also be noted in diabetes mellitus, systemic lupus erythematosus, hemolytic-uremic syndrome, chronic inflammatory bowel diseases (Crohn’s disease or ulcerative colitis) and sickle cell anemia.

An increase in the frequency and severity of migraine during the use of Jess^® Plus (which may precede cerebrovascular disorders) is grounds for immediate discontinuation of the drug.

Biochemical indicators indicating a hereditary or acquired predisposition to venous or arterial thrombosis include the following: resistance to activated protein C, hyperhomocysteinemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).

When assessing the risk-benefit ratio, it should be taken into account that adequate treatment of the corresponding condition may reduce the associated risk of thrombosis. It should also be taken into account that the risk of thrombosis and thromboembolism during pregnancy is higher than when taking low-dose oral contraceptives (<0.05 mg ethinyl estradiol).

Tumors

The most significant risk factor for cervical cancer is persistent human papillomavirus infection. There are reports of a slight increase in the risk of developing cervical cancer with long-term use of COCs. However, the connection with COC use has not been proven. The possibility of a connection between these data with cervical disease screening and sexual behavior characteristics (less frequent use of barrier contraceptive methods) is discussed.

A meta-analysis of 54 epidemiological studies showed that there is a slightly increased relative risk of breast cancer diagnosed in women currently taking COCs (relative risk 1.24). The increased risk gradually disappears within 10 years after stopping these drugs. Since breast cancer is rare in women under 40 years of age, the increase in the number of breast cancer diagnoses in women currently taking or recently taking COCs is insignificant relative to the overall risk of this disease. Its connection with COC use has not been proven. The observed increase in risk may be a consequence of careful monitoring and earlier diagnosis of breast cancer in women using COCs, the biological effect of sex hormones, or a combination of both factors. In women who have ever used COCs, earlier stages of breast cancer are detected than in women who have never used them.

In rare cases, the development of benign, and in extremely rare cases, malignant liver tumors has been observed during the use of COCs, which in some patients led to life-threatening intra-abdominal bleeding. If severe abdominal pain, liver enlargement or signs of intra-abdominal bleeding appear, this should be taken into account when making a differential diagnosis.

Other conditions

Clinical studies have shown no effect of drospirenone on plasma potassium concentration in patients with mild to moderate renal failure. However, in patients with impaired renal function and baseline potassium concentration at the upper limit of normal, the risk of developing hyperkalemia while taking drugs that lead to potassium retention in the body cannot be excluded.

In women with hypertriglyceridemia (or a family history of this condition), the risk of developing pancreatitis may increase while taking COCs.

Although a slight increase in blood pressure has been described in many women taking COCs, clinically significant increases have been rare. However, if a persistent, clinically significant increase in blood pressure develops during the use of Jess^® Plus, this drug should be discontinued and treatment for arterial hypertension should be started. Taking the drug can be continued if normal blood pressure values are achieved with antihypertensive therapy.

The following conditions have been reported to develop or worsen both during pregnancy and when taking COCs, but their connection with COC use has not been proven: jaundice and/or pruritus associated with cholestasis; formation of gallstones; porphyria; systemic lupus erythematosus: hemolytic-uremic syndrome; Sydenham’s chorea; herpes during pregnancy; hearing loss associated with otosclerosis. Cases of worsening of endogenous depression, epilepsy, Crohn’s disease and ulcerative colitis during the use of COCs have also been described.

In women with hereditary forms of angioedema, exogenous estrogens may cause or worsen the symptoms of angioedema.

Acute or chronic liver dysfunction may require discontinuation of Jess^® Plus until liver function tests return to normal. Recurrence of cholestatic jaundice that first developed during a previous pregnancy or previous use of sex hormones requires discontinuation of Jess^® Plus.

Although COCs may affect insulin resistance and glucose tolerance, there is usually no need to adjust the dose of hypoglycemic drugs in patients with diabetes using low-dose combined oral contraceptives (<0.05 mg ethinyl estradiol). However, women with diabetes require careful monitoring while using COCs.

Chloasma may sometimes develop, especially in women with a history of chloasma of pregnancy. Women prone to chloasma while taking Jess^® Plus should avoid prolonged exposure to the sun and ultraviolet radiation.

Folate may mask vitamin B₁₂ deficiency.

Laboratory tests

Taking Jess^® Plus may affect the results of some laboratory tests, including indicators of liver, kidney, thyroid, adrenal function, the concentration of transport proteins in plasma, indicators of carbohydrate metabolism, parameters of blood coagulation and fibrinolysis. The changes usually do not go beyond the normal limits. Drospirenone increases plasma renin activity and aldosterone concentration, which is associated with its antimineralocorticoid effect.

Reduced effectiveness

The contraceptive effectiveness of Jess^® Plus may be reduced in the following cases: when missing pink tablets, gastrointestinal disorders while taking pink tablets, or as a result of drug interactions.

Frequency and severity of menstrual-like bleeding

During the first few months of taking Jess^® Plus, irregular (acyclic) vaginal bleeding (“spotting” and/or “breakthrough” uterine bleeding) may be observed. Hygiene products should be used and tablets should be continued as usual. Evaluation of any irregular bleeding should be carried out after an adaptation period of approximately 3 cycles of taking the drug.

If irregular bleeding recurs or develops after previous regular cycles, a thorough examination should be carried out to exclude malignant neoplasms or pregnancy.

Absence of scheduled menstrual-like bleeding

Some women may not develop withdrawal bleeding while taking the auxiliary light-orange tablets. If Jess^® Plus was taken according to the recommendations, it is unlikely that the woman is pregnant. However, if the regimen for taking Jess^® Plus was not followed and two consecutive withdrawal bleedings are absent, taking the drug cannot be continued until pregnancy is excluded.

Medical examinations

Before starting or resuming use of the drug, it is necessary to review the woman’s life history, family history, conduct a thorough physical examination (including measurement of blood pressure, heart rate, determination of BMI, breast examination), gynecological examination, cytological examination of the cervix (Pap test), and exclude pregnancy. When resuming taking Jess^® Plus, the scope of additional studies and the frequency of follow-up examinations are determined individually, but not less than once every 6 months.

The woman must be warned that Jess^® Plus does not protect against HIV infection and other sexually transmitted diseases.

Conditions requiring medical consultation

• Any changes in health, especially the occurrence of conditions listed in the sections “Contraindications” and “With caution”;
• Local lump in the breast;
• Concomitant use of other drugs (see section “Drug Interactions”);
• If prolonged immobility is expected (for example, a cast is applied to a lower limb), hospitalization or surgery is planned (at least 4 weeks before the planned surgery);
• Unusually heavy vaginal bleeding;
• A tablet was missed in the first week of taking the pack and there was sexual intercourse 7 or fewer days before that;
• Absence of scheduled menstrual-like bleeding 2 times in a row or suspicion of pregnancy (you should not start taking tablets from the next pack until consulting a doctor).

You should stop taking the tablets and immediately consult a doctor if there are possible signs of thrombosis, myocardial infarction or stroke: unusual cough; unusually severe pain behind the breastbone, radiating to the left arm; unexpectedly occurring shortness of breath, unusual, severe and prolonged headache or migraine attack; partial or complete loss of vision or double vision; slurred speech; sudden changes in hearing, smell or taste; dizziness or fainting; weakness or loss of sensation in any part of the body; severe abdominal pain; severe pain in the lower limb or sudden swelling of any of the lower limbs.

Effect on the Ability to Drive Vehicles and Operate Machinery

No cases of adverse effects of the drug Jess^® Plus on the speed of psychomotor reactions have been reported; studies on the effect of the drug on the speed of psychomotor reactions have not been conducted.

Overdose

No cases of overdose with the drug Jess^® Plus have been reported.

Symptoms that may occur with overdose: nausea, vomiting, and withdrawal bleeding. The latter may occur in girls who have not reached menarche age due to accidental ingestion of the drug.

Treatment: there is no specific antidote, symptomatic treatment should be carried out.

Calcium levomefolate and its metabolites are identical to folates found in natural products, the daily consumption of which is not harmful to the body. Intake of calcium levomefolate at a dose of 17 mg/day (a dose 37 times higher than that contained in 1 tablet of Jess^® Plus) for up to 12 weeks was well tolerated by patients.

Drug Interactions

Effect of Other Drugs on Jess^® Plus

Interaction with drugs that induce liver microsomal enzymes is possible, which may increase the clearance of sex hormones, which, in turn, may lead to breakthrough uterine bleeding and/or a decrease in the contraceptive effect.

Induction of liver microsomal enzymes may be observed within a few days of treatment. Maximum induction of liver microsomal enzymes is usually observed within a few weeks. After discontinuation of the drug, induction of liver microsomal enzymes may persist for 4 weeks.

Short-term therapy

Women who are receiving treatment with such drugs in addition to Jess^® Plus are advised to use a barrier method of contraception or choose another non-hormonal method of contraception. The barrier method of contraception should be used throughout the period of taking the concomitant drugs, as well as for 28 days after their discontinuation. If the use of the liver microsomal enzyme inducer needs to be continued after the pink (hormone-containing) tablets are finished, the intake of light orange (placebo) tablets should be skipped and the intake of Jess^® Plus tablets from a new package should be started.

Long-term therapy

Women who are taking drugs that are liver microsomal enzyme inducers long-term are advised to use another reliable non-hormonal method of contraception.

Drugs that increase the clearance of Jess^® Plus (weakening effectiveness by enzyme induction): phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, as well as preparations containing St. John’s wort.

Drugs with variable effects on the clearance of Jess^® Plus when used concomitantly with Jess^® Plus, many HIV or hepatitis C virus protease inhibitors and non-nucleoside reverse transcriptase inhibitors can either increase or decrease the plasma concentrations of estrogens or progestins. In some cases, this effect may be clinically significant.

Drugs that reduce the effectiveness of calcium levomefolate some medications reduce plasma folate concentrations and reduce the effectiveness of folates by inhibiting the enzyme dihydrofolate reductase (for example, methotrexate, trimethoprim, sulfasalazine, and triamterene) or by reducing folate absorption (for example, cholestyramine) or by unknown mechanisms (for example, antiepileptic drugs – carbamazepine, phenytoin, phenobarbital, primidone, and valproic acid).

Drugs that decrease the clearance of COCs (enzyme inhibitors) strong and moderate inhibitors of CYP3A4, such as azole antifungals (for example, itraconazole, voriconazole, fluconazole), verapamil, macrolide antibiotics (for example, clarithromycin, erythromycin), diltiazem, and grapefruit juice may increase plasma concentrations of estrogen or progestin, or both.

Etoricoxib at doses of 60 and 120 mg/day when co-administered with COCs containing 0.035 mg ethinylestradiol was shown to increase plasma concentrations of ethinylestradiol by 1.4 and 1.6 times, respectively.

Effect of COCs or Calcium Levomefolate on Other Drugs

COCs may affect the metabolism of other drugs, leading to an increase (for example, cyclosporine) or decrease (for example, lamotrigine) in their plasma and tissue concentrations.

In vitro, Drospirenone is able to weakly or moderately inhibit the cytochrome P450 enzymes CYP1A1, CYP2C9, CYP2C19, and CYP3A4.

Based on in vivo interaction studies in female volunteers taking omeprazole, simvastatin, or midazolam as marker substrates, it can be concluded that a clinically significant effect of 3 mg drospirenone on drug metabolism mediated by cytochrome P450 enzymes is unlikely.

In vitro, Ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1, and CYP1A2, as well as an irreversible inhibitor of CYP3A4/5, CYP2C8, and CYP2J2. In clinical studies, the administration of a hormonal contraceptive containing Ethinylestradiol did not lead to any increase or led only to a weak increase in plasma concentrations of CYP3A4 substrates (for example, midazolam), while plasma concentrations of CYP1A2 substrates may increase weakly (for example, theophylline) or moderately (for example, melatonin and tizanidine).

Folates may alter the pharmacokinetics or pharmacodynamics of some drugs affecting folate metabolism, for example, antiepileptic drugs (phenytoin), methotrexate, or pyrimethamine, which may be accompanied by a decrease (mainly reversible, provided the dose of the drug affecting folate metabolism is increased) in their therapeutic effect. The administration of folates during treatment with such drugs is recommended mainly to reduce the toxicity of the latter.

Pharmacodynamic Interaction

Concomitant use of ethinylestradiol-containing drugs and direct-acting antiviral drugs containing ombitasvir, paritaprevir, dasabuvir, or their combination has been shown to be associated with an increase in ALT activity of more than 20 times the upper limit of normal in healthy and hepatitis C virus-infected women (see the “Contraindications” section).

Other Forms of Interaction

In patients with unimpaired renal function, the combined use of drospirenone and ACE inhibitors or NSAIDs does not have a significant effect on plasma potassium concentration. However, the combined use of Jess^® Plus with aldosterone antagonists or potassium-sparing diuretics has not been studied. In such cases, plasma potassium concentration should be monitored during the first cycle of administration.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the package.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.