Yarina Plus, 84 pcs.

Yarina®Plus is a low-dose monophasic combined estrogen/gestagen contraceptive consisting of hormone tablets and adjunctive tablets containing calcium levomepolate.

The contraceptive effect of Yarina®Plus is mainly due to suppression of ovulation and increased cervical secretion viscosity.

In women taking combined oral contraceptives (OCs), the cycle becomes more regular, pain, intensity and duration of menstrual bleeding decrease, and as a result the risk of iron deficiency anemia decreases. There is also evidence of a decreased risk of endometrial and ovarian cancer.

Two post-registration studies were conducted to assess the risk of VTE with Yarin® (ethinylestradiol/drospirenone at doses of 0.03 mg/3 mg). The first prospective observational study showed that the incidence of VTE in women using Yarina®, with or without other VTE risk factors, was in the same range as for women using levonorgestrel and other OCs. A second prospective controlled database study comparing women using Yarin® with women using other OCs also confirmed similar rates of VTE among all cohorts of women.

Drospirenone in Yarina® Plus has antimineralocorticoid activity and helps prevent hormone-dependent fluid retention, which may be seen in weight loss and decreased likelihood of peripheral edema.

Drospirenone also has anti-androgenic activity and helps to reduce acne (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 women with acne and seborrhea. In its characteristics drospirenone is similar to natural progesterone produced by the female body.

When the drug is used correctly, the Perl index (a measure of the number of pregnancies in 100 women using the contraceptive in a year) is less than 1. If the pill is missed or used incorrectly, the Perl Index may increase.

The acidic form of calcium levomepholate is identical in structure to naturally occurring L- 5-methyltetrahydrofolate (L-5-methyl-THF), the major folate form found in food. The average plasma concentration of L-5-methyltetrahydrofolate in people who do not use foods fortified with folic acid is about 15 nmol/L.

Levomefolate, unlike folic acid, is a biologically active form of folate. Because of this it is absorbed better than folic acid. Levomefolate is indicated to meet the increased demand and to ensure the necessary content of folate in women during pregnancy and during breastfeeding.

The introduction of calcium levomepholate as part of an oral contraceptive reduces the risk of fetal neural tube defects if a woman becomes pregnant immediately after discontinuation of contraception (or, in very rare cases, when using oral contraception).

Indications

Contraception intended primarily for women with symptoms of hormone-dependent fluid retention in the body.
Contraception and treatment of moderate forms of acne (acne vulgaris).
Contraception in women with folate deficiency.

Pharmacological effect

The drug Yarina®Plus is a low-dose monophasic combined estrogen-progestogen contraceptive drug, consisting of tablets containing hormones and auxiliary tablets containing calcium levomefolate.

The contraceptive effect of the drug Yarina®Plus is mainly achieved by suppressing ovulation and increasing the viscosity of cervical secretions.

In women taking combined oral contraceptives (COCs), the cycle becomes more regular, the pain, intensity and duration of menstrual bleeding decrease, resulting in a reduced risk of iron deficiency anemia. There is also evidence of a reduced risk of endometrial and ovarian cancer.

To assess the risk of VTE with the use of Yarina® (ethinyl estradiol/drospirenone in doses of 0.03 mg/3 mg), two post-registration studies were conducted. The first prospective observational study showed that the incidence of VTE in women using Yarina®, with or without other risk factors for VTE, was in the same range as for women using levonorgestrel-containing and other COCs. A second prospective controlled database study comparing women using Yarina with women using other COCs also confirmed similar rates of VTE among all cohorts of women.

Drospirenone, which is part of the drug Yarina® Plus, has antimineralocorticoid activity and helps prevent hormone-dependent fluid retention, which can manifest itself in weight loss and a decrease in the likelihood of peripheral edema.

Drospirenone also has antiandrogenic activity and helps reduce acne, oily skin and hair (seborrhea). These features of drospirenone should be taken into account when choosing a contraceptive for women with hormone-dependent fluid retention, as well as women with acne and seborrhea. According to its characteristics, drospirenone is similar to natural progesterone produced by the female body.

When the drug is used correctly, the Pearl index (an indicator reflecting the number of pregnancies in 100 women using contraception during the year) is less than 1. If pills are missed or the drug is used incorrectly, the Pearl index may increase.

The acid form of calcium levomefolate is structurally identical to naturally occurring 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 who do not consume food fortified with folic acid is about 15 nmol/L.

Levomefolate, unlike folic acid, is a biologically active form of folate. Thanks to this, it is absorbed better than folic acid. Levomefolate is indicated to meet the increased need and ensure the necessary folate content in a woman’s body during pregnancy and breastfeeding.

The addition of calcium levomefolate to an oral contraceptive reduces the risk of developing a neural tube defect if a woman becomes pregnant immediately after stopping contraception (or, in very rare cases, when using oral contraception).

Special instructions

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

Diseases of the cardiovascular system

There is epidemiological evidence of an increased incidence of venous and arterial thrombosis and thromboembolism (such as deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) when taking combined oral contraceptives. These diseases are rarely observed.

The risk of developing venous thromboembolism (VTE) is greatest in the first year of using such drugs. An increased risk is present after initial use of combined oral contraceptives or resumption of use of the same or different combined oral contraceptives (after a dosing interval of 4 weeks or more). Data from a large prospective study involving 3 groups of patients suggest that this increased risk is predominantly present during the first 3 months.

The overall risk of VTE in patients taking low-dose combined oral contraceptives (<50 mcg ethinyl estradiol) is 2-3 times higher than in non-pregnant patients not taking combined oral contraceptives, however, this risk remains lower than the risk of VTE during pregnancy and childbirth.

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

VTE, manifested as deep vein thrombosis or pulmonary embolism, can occur with the use of any combined oral contraceptives.

It is extremely rare when using combined oral contraceptives that thrombosis of other blood vessels occurs, for example, hepatic, mesenteric, renal, cerebral veins and arteries or retinal vessels. There is no consensus regarding the relationship between the occurrence of these events and the use of combined oral contraceptives.

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

Symptoms of pulmonary embolism (PE): difficulty or rapid breathing; sudden cough, incl. with hemoptysis; sharp pain in the chest, which may intensify with deep inspiration; feeling of anxiety; severe dizziness; fast or irregular heartbeat. Some of these symptoms (eg, shortness of breath, cough) are nonspecific and may be misinterpreted as signs of other more or less severe events (eg, respiratory tract infection).

Arterial thromboembolism can lead to stroke, vascular occlusion, or myocardial infarction. Symptoms of a stroke: sudden weakness or loss of sensation in the face, upper or lower extremities, especially on one side of the body; sudden confusion, problems with speech and understanding; sudden unilateral or bilateral vision loss; sudden disturbance in gait, dizziness, loss of balance or coordination; sudden, severe or prolonged headache for no apparent reason; loss of consciousness or fainting with or without an epileptic seizure. Other signs of vascular occlusion: sudden pain, swelling and slight blue discoloration of the extremities, the “acute abdomen” symptom complex.

Symptoms of myocardial infarction: pain, discomfort, pressure, heaviness, a feeling of squeezing or fullness in the chest, arm or chest; discomfort radiating to the back, cheekbone, larynx, arm, stomach; cold sweat, nausea, vomiting or dizziness, severe weakness, anxiety or shortness of breath; fast or irregular heartbeat.

Arterial thromboembolism can be life-threatening or fatal.

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

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

– with age;

– in smokers (with an increase in the number of cigarettes or an increase in age, the risk increases, especially in women over 35 years of age);

if available:

— obesity (BMI more than 30 kg/m2);

– indications in family history (for example, venous or arterial thromboembolism ever in close relatives or parents at a relatively young age). In the case of a hereditary or acquired predisposition, the woman should be referred to a specialist to decide on the possibility of using the drug Yarina® Plus;

– prolonged immobilization, major surgery, any operation on the lower extremities or major trauma. In these situations, it is advisable to stop using the drug Yarina® Plus (in the case of a planned operation, at least 4 weeks before it) and not to resume taking it for 2 weeks after the end of immobilization;

– dislipoproteinemia;

– arterial hypertension;

– migraine;

— diseases of the heart valves;

– atrial fibrillation.

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 occur in diabetes mellitus, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease (Crohn’s disease or UC), and sickle cell anemia.

An increase in the frequency and severity of migraine during use of Yarina®Plus (which may precede cerebrovascular events) may be grounds for immediate discontinuation of this 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, antibodies to phospholipids (anticardiolipin antibodies, lupus anticoagulant).

When assessing the risk-benefit ratio, it should be taken into account that adequate treatment of the relevant condition can 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 (<50 mcg ethinyl estradiol).

Tumors

The most significant risk factor for developing 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 combined oral contraceptives. However, the connection with the use of combined oral contraceptives has not been proven. The possibility of the relationship of these data with screening for cervical diseases and with characteristics of sexual behavior (less frequent use of barrier methods of contraception) is discussed.

A meta-analysis of 54 epidemiological studies found that there is a slightly increased relative risk of developing breast cancer diagnosed in women currently taking combined oral contraceptives (relative risk 1.24). The increased risk gradually disappears within 10 years of stopping these drugs. Because breast cancer is rare in women under 40 years of age, the increase in breast cancer diagnoses in women currently or recently taking combined oral contraceptives is small relative to the overall risk of breast cancer. Its connection with the use of combined oral contraceptives has not been proven. The observed increased risk may be a consequence of careful monitoring and earlier diagnosis of breast cancer in women using combined oral contraceptives. Women who have ever used combined oral contraceptives are diagnosed with earlier stages of breast cancer than women who have never used them.

In rare cases, during the use of combined oral contraceptives, the development of benign, and in extremely rare cases, malignant liver tumors was observed, which in some patients led to life-threatening intra-abdominal bleeding.

If severe abdominal pain, liver enlargement, or signs of intra-abdominal bleeding occur, this should be taken into account when making a differential diagnosis.

Other states

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

Women with hypertriglyceridemia (or a family history of this condition) may have an increased risk of developing pancreatitis while taking combined oral contraceptives.

Although slight increases in blood pressure have been described in many women taking combined oral contraceptives, clinically significant increases have rarely been observed. However, if a persistent, clinically significant increase in blood pressure develops while using Yarina® Plus, this drug should be discontinued and treatment of arterial hypertension should be started. 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 during the use of combined oral contraceptives, but their relationship with the use of combined oral contraceptives 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 Crohn’s disease and ulcerative colitis have also been described during the use of combined oral contraceptives.

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

Acute or chronic liver dysfunction may require discontinuation of Yarina® Plus until liver function tests return to normal. Recurrent cholestatic jaundice, which develops for the first time during pregnancy or during a previous intake of sex hormones, requires discontinuation of the drug Yarina® Plus.

Although combined oral contraceptives may have an effect on insulin resistance and glucose tolerance, there is no need to change the therapeutic regimen in diabetic patients using Yarina® Plus. However, women with diabetes should be closely monitored while using this drug.

Chloasma can sometimes develop, especially in women with a history of chloasma during pregnancy. Women with a tendency to chloasma while taking Yarina® Plus should avoid prolonged exposure to the sun and exposure to ultraviolet radiation.

Folates may mask vitamin B12 deficiency.

Preclinical safety data

Preclinical data from routine repeated-dose toxicity, genotoxicity, carcinogenicity and reproductive toxicity studies do not indicate a particular risk to humans. However, it should be remembered that sex hormones can promote the growth of certain hormone-dependent tissues and tumors.

Laboratory tests

Taking Yarina® 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. Changes usually do not go beyond normal values. Drospirenone increases plasma renin activity and aldosterone concentrations, which is associated with its antimineralocorticoid effect.

There is a theoretical possibility of increasing the concentration of potassium in the blood plasma in women receiving Yarina® Plus simultaneously with other drugs that can increase the content of potassium in the blood plasma. These drugs include angiotensin II receptor antagonists, potassium-sparing diuretics, and aldosterone antagonists. However, in studies evaluating the interaction of drospirenone with ACE inhibitors or indomethacin, there was no significant difference in plasma potassium concentrations compared with placebo.

Reduced efficiency

The effectiveness of Yarina® Plus may be reduced in the following cases: if you miss pills, with gastrointestinal disorders or as a result of drug interactions.

Frequency and severity of menstrual bleeding

While using the drug Yarina® Plus, irregular (acyclic) spotting and bleeding from the vagina (spotting or breakthrough uterine bleeding) may occur, especially during the first months of use. You should use hygiene products and continue taking your tablets as usual. Any irregular bleeding should be assessed after an adaptation period of approximately 3 cycles.

If irregular bleeding recurs or develops after previous regular cycles, careful evaluation should be performed to rule out malignancy or pregnancy.

Some women may not develop withdrawal bleeding during a pill-free break. If Yarina® Plus was taken as recommended, it is unlikely that the woman is pregnant. However, if the drug Yarina® Plus is not used regularly and there are no two withdrawal bleedings in a row, the drug cannot be continued until pregnancy has been ruled out.

Medical examinations

Before starting or resuming use of the drug, it is necessary to familiarize yourself with the woman’s life history, family history, conduct a thorough physical examination (including measuring blood pressure, heart rate, determining BMI, examining the mammary glands), gynecological examination, cytological examination of the cervix (Papanicolaou test), and exclude pregnancy. When resuming taking the drug Yarina® Plus, the volume of additional studies and the frequency of control examinations are determined individually, but at least once every 6 months.

The woman should be warned that Yarina® 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 “Precautions”;

– local compaction in the mammary gland;

– simultaneous use of other medications (see section “Drug interactions”);

– if prolonged immobility is expected (for example, a cast is applied to the lower limb), hospitalization or surgery is planned (at least 3-4 weeks before the proposed operation);

– unusually heavy bleeding from the vagina;

– missed a pill in the first week of taking the package and had sexual intercourse 7 days or less before;

– absence of regular menstrual-like bleeding 2 times in a row or suspicion of pregnancy (you should not start taking pills from the next package before consulting your doctor).

You should stop taking the tablets and consult your doctor immediately if there are possible signs of thrombosis, myocardial infarction or stroke: unusual cough; unusually severe pain behind the sternum, radiating to the left arm; unexpected 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.

Impact on the ability to drive vehicles and operate machinery

There have been no reported cases of adverse effects of the drug Yarina® Plus on the speed of psychomotor reactions; No studies have been conducted to study the effect of the drug on the speed of psychomotor reactions.

Active ingredient

Drospirenone, Ethinyl estradiol, Calcium Levomefolinate

Composition

Film-coated tablets (active combination)

1 tablet contains:

active substances:

ethinyl estradiol (micronized, in the form of betadex clathrate) 30 mcg,

drospirenone (micronized) 3 mg,

calcium levomefolate (micronized) 451 mcg

excipients:

lactose monohydrate – 45.319 mg,

microcrystalline cellulose – 24.8 mg,

croscarmellose sodium – 3.2 mg,

hyprolose (5 cP) – 1.6 mg,

magnesium stearate – 1.6 mg.

shell composition:

orange varnish – 2 mg or (alternatively):

hypromellose (5 cP) – 1.0112 mg,

macrogol 6000 – 202.4 mcg,

talc – 202.4 mcg,

titanium dioxide – 527.1 mcg,

iron oxide yellow dye – 44.6 mcg,

red iron oxide dye – 12.3 mcg.

Film-coated tablets (vitamin supplements)

1 tablet contains:

active substances:

calcium levomefolate (micronized) 451 mg

excipients:

lactose monohydrate – 48.349 mg,

microcrystalline cellulose – 24.8 mg,

croscarmellose sodium – 3.2 mg,

hyprolose (5 cP) – 1.6 mg,

magnesium stearate – 1.6 mg.

shell composition:

light orange varnish – 2 mg or (alternatively):

hypromellose (5 cP) – 1.0112 mg,

macrogol 6000 – 202.4 mcg,

talc – 202.4 mcg,

titanium dioxide – 572.3 mcg,

iron oxide yellow dye – 8.9 mcg,

red iron oxide dye – 2.8 mcg.

Pregnancy

The drug is contraindicated during pregnancy. If pregnancy is detected while taking Yarina Plus, the drug should be discontinued immediately.

Data on the results of taking the drug Yarina Plus during pregnancy are limited and do not allow us to draw any conclusions about the negative impact of the drug on pregnancy, the health of the fetus and newborn child.

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 teratogenic effects in cases of inadvertent use of COCs in early pregnancy. Specific epidemiological studies have not been conducted regarding the drug YarinaPlus.

Lactation

The drug is contraindicated during breastfeeding. Taking COCs can reduce the amount of breast milk and change its composition, so their use is not recommended until breastfeeding is stopped. Small amounts of sex hormones and/or their metabolites may be excreted in milk, but there is no evidence of their negative effects on the health of the child.

Contraindications

Yarina Plus is contraindicated in the presence of any of the conditions/diseases listed below. If any of these conditions/diseases develop for the first time while taking the drug, the drug should be discontinued immediately.

Thrombosis (venous and arterial) and thromboembolism currently or in history (including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke), cerebrovascular disorders.
Conditions preceding thrombosis (including transient ischemic attacks, angina) currently or in history.
The presence of multiple or severe risk factors for venous or arterial thrombosis.
Liver failure and severe liver diseases (until liver tests normalize).
Severe and/or acute renal failure.
Liver tumors (benign or malignant) currently or in history.
Migraine with focal neurological symptoms currently or in history.
Diabetes mellitus with vascular complications.
Detected hormone-dependent malignant neoplasms (including genitals or mammary glands) or suspicion of them.
Bleeding from the vagina of unknown origin.
Hypersensitivity or intolerance to any of the components of the drug Yarina Plus.
Yarina Plus contains lactose and is therefore contraindicated in patients with rare hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption.
Pregnancy or suspicion of it.
Breastfeeding period.

With caution
The potential risk and expected benefit of using the drug Yarina Plus should be assessed in each individual case in the presence of the following diseases/conditions and risk factors:

Risk factors for the development of thrombosis and thromboembolism: smoking, obesity, dyslipoproteinemia, controlled arterial hypertension, migraine without focal neurological symptoms, uncomplicated valvular heart disease, hereditary predisposition to thrombosis (thrombosis, myocardial infarction or cerebrovascular accident at a young age in one of the immediate family);
Other diseases in which peripheral circulatory disorders may occur: diabetes mellitus without vascular complications, systemic lupus erythematosus, hemolytic-uremic syndrome, Crohn’s disease and ulcerative colitis, sickle cell anemia, phlebitis of the superficial veins;
Hereditary angioedema;
Hypertriglyceridemia:
Liver diseases that are not contraindications (see “Contraindications”);
Diseases that first appeared or worsened during pregnancy or against the background of previous use of sex hormones (for example, jaundice and/or itching associated with cholestasis, cholelithiasis, otosclerosis with hearing impairment, porphyria, pregnancy herpes, Sydenham’s chorea);
Postpartum period.

Side Effects

From the immune system: frequency unknown – hypersensitivity reactions.

From the side of metabolism and nutrition: infrequently – changes in body weight, fluid retention.

Mental disorders: often – depressed mood; infrequently – changes in libido; frequency unknown – mood swings.

From the nervous system: often – headache, migraine.

On the part of the organ of vision: frequency unknown – intolerance to contact lenses.

From the organ of hearing: rarely – hypoacusis.

From the cardiovascular system: infrequently – increased blood pressure, decreased blood pressure; rarely – thromboembolism.

From the respiratory system: rarely – bronchial asthma.

From the gastrointestinal tract: often – nausea; infrequently – vomiting; frequency unknown – abdominal pain, diarrhea.

From the skin and subcutaneous tissues: infrequently – acne, eczema, itching, alopecia; frequency unknown – rash, urticaria, erythema nodosum, erythema multiforme.

From the genital organs and breast: often – pain in the mammary glands (including engorgement of the mammary glands), tenderness of the mammary glands, leucorrhoea (including vaginal discharge), vulvovaginal candidiasis, absence of menstrual-like bleeding, painful menstrual-like bleeding, heavy menstrual-like bleeding, scanty menstrual-like bleeding, absence of menstrual-like bleeding, acyclic bleeding (usually decreases with prolonged use of the drug); infrequently – vaginitis; rarely – discharge from the mammary glands; frequency unknown – enlargement of the mammary glands.

Interaction

The influence of other drugs on the drug Yarina®Plus

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

Women who are treated with such drugs in addition to Yarina® Plus are recommended to temporarily use a barrier method of contraception or choose another non-hormonal method of contraception. A barrier method of contraception should be used during the entire period of taking concomitant medications, as well as for 28 days after their discontinuation. If the period of use of the barrier method of contraception ends later than the orange (active) tablets in the package of Yarina® Plus, you should skip taking the light orange (auxiliary) tablets and start taking tablets from the new package of Yarina® Plus.

Agents that increase the clearance of Yarina® Plus (weakening the effectiveness by inducing enzymes): phenytoin, barbiturates, primidone, carbamazepine, rifampicin and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, as well as drugs containing St. John’s wort.

Agents with different effects on the clearance of Yarina® Plus: when used together with Yarina® Plus, many HIV or hepatitis C virus protease inhibitors and non-nucleoside reverse transcriptase inhibitors can either increase or decrease the concentration of estrogens or progestins in the blood plasma. In some cases, this effect may be clinically significant.

Drugs that reduce the effectiveness of levomefolate calcium: Some drugs 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 the absorption of folates (for example, cholestyramine) or through unknown mechanisms (for example, antiepileptic drugs: carbamazepine, phenytoin, phenobarbital, primidone and valproic acid).

Drugs that reduce the clearance of combined oral contraceptives (enzyme inhibitors): strong and moderate inhibitors of CYP3A4, such as azole antifungals (eg, itraconazole, voriconazole, fluconazole), verapamil, macrolide antibiotics (eg, clarithromycin, erythromycin), diltiazem and grapefruit juice may increase plasma concentrations estrogen or progestin, or both.

Etoricoxib at doses of 60 and 120 mg/day, when coadministered with combined oral contraceptives containing 0.035 mg ethinyl estradiol, has been shown to increase plasma concentrations of ethinyl estradiol by 1.4 and 1.6 times, respectively.

Effect of combined oral contraceptives or calcium levomefolate on other drugs

Combined oral contraceptives may affect the metabolism of other drugs, resulting in an increase (for example, cyclosporine) or a decrease (for example, lamotrigine) in their plasma and tissue concentrations.

In vitro, drospirenone is capable of weakly to moderate inhibition of 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 drospirenone 3 mg on cytochrome P450-mediated drug metabolism is unlikely.

In vitro, ethinyl estradiol is a reversible inhibitor of CYP2C19, CYP1A1 and CYP1A2, and an irreversible inhibitor of CYP3A4/5, CYP2C8 and CYP2J2. In clinical studies, administration of a hormonal contraceptive containing ethinyl estradiol did not result in any increase or only a slight increase in plasma concentrations of CYP3A4 substrates (e.g., midazolam), whereas plasma concentrations of CYP1A2 substrates may increase weakly (e.g., theophylline) or moderately (e.g., melatonin and tizanidine).

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

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 the concentration of potassium in the blood plasma. However, the combined use of Yarina®Plus with aldosterone antagonists or potassium-sparing diuretics has not been studied. In such cases, the concentration of potassium in the blood plasma must be monitored during the first cycle of dosing.

Overdose

No cases of overdose of Yarina® Plus have been reported.

Symptoms that may occur in case of overdose: nausea, vomiting, spotting vaginal discharge or metrorrhagia (more often in young women).

Treatment: there is no specific antidote; symptomatic treatment should be carried out. Calcium levomefolate and its metabolites are identical to folates found in food products, the daily consumption of which does not harm the body. Taking levomefolate calcium at a dose of 17 mg/day (the dose is 37 times higher than that contained in 1 tablet of Yarina® Plus) for 12 weeks was well tolerated.

Storage conditions

At a temperature not exceeding 25 °C. Keep out of the reach of children.

Shelf life

2 years

Manufacturer

Bayer Weimar GmbH & Co. KG, Germany