Dimia, 3 mg+0.02 mg 84 pcs

The drug Dimia is a combined monophasic oral contraceptive containing drospirenone and ethinylestradiol.

Indications

Active ingredient

Composition

Ethinylestradiol+drospirenone tablets

1 tablet contains:

active ingredients:

ethinylestradiol 0.02 mg,

rospirenone 3 mg,

excipients:

Lactose monohydrate, 48.53 mg;

Corn starch, 16.6 mg;

Pregelatinized corn starch – 9.6 mg;

Macrogoal and polyvinyl alcohol copolymer – 1.45 mg;

Magnesium stearate – 0.8 mg,

coat film:

Opadry II white 85G18490 (polyvinyl alcohol – 0.88 mg, titanium dioxide – 0.403 mg, macrogol 3350 – 0.247 mg, talc – 0.4 mg, soy lecithin – 0.07 mg) – 2 mg

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Placebo tablets

1 tablet contains:

MCC – 42.39 mg;

Lactose – 37.26 mg;

Pregelatinized corn starch – 9 mg;

magnesium stearate – 0.9 mg;

colloidal silica – 0.45 mg,

film coating:

Opadry II green 85F21389 (polyvinyl alcohol – 1.2 mg, titanium dioxide – 0.7086 mg, macrogol 3350 – 0.606 mg, talc – 0.444 mg, indigo carmine – 0.0177 mg, quinoline yellow dye – 0.0177 mg, iron oxide black dye – 0.003 mg, sunset yellow dye – 0.003 mg) – 3 mg.

How to take, the dosage

Inhaled, daily, at approximately the same time, washed down with a small amount of water, in the order shown on the blister pack. The tablets are taken continuously for 28 days, 1 tablet a day. Taking tablets from the next package begins after taking the last tablet from the previous package. Withdrawal bleeding usually begins on the 2nd or 3rd day after starting the placebo pills (last row) and does not necessarily end by the beginning of the next pack.

The order of taking Dimia®

Hormonal contraceptives were not used in the last month. Taking Dimia® starts on the 1st day of menstrual cycle (i.e. on the 1st day of menstrual bleeding). It is possible to start taking it on the 2nd-5th day of a menstrual cycle; in this case an additional use of a barrier method of contraception during the first 7 days of taking tablets from the first package is necessary.

Transition from other combined contraceptives (OC in the form of pills, vaginal ring or transdermal patch). Starting Dimia® ® the day after taking the last inactive pill (for products containing 28 pills) or the day after taking the last active pill from the previous package (and possibly the day after the usual 7-day interval) for products containing 21 pills per package. If a woman uses a vaginal ring or a transdermal patch, it is preferable to start Dimia® on the day they are removed or, at the latest, on the day the new ring or patch is planned.

The transition from progestagen-only contraceptives (mini-pills, injectables, implants) or from a progestagen-releasing intrauterine system (IUD). A woman may switch from taking mini-pills to taking Dimia® on any day (from the implant or IUD – on the day of their removal, from injectable forms of drugs – on the day when the next injection should have been made), but in all cases it is necessary to use an additional barrier method of contraception for the first 7 days of taking the pills.

After an abortion in the first trimester of pregnancy. The use of the drug Dimia ® may be started by prescription on the day of abortion. In this case a woman does not need to take additional contraceptive measures.

After childbirth or abortion in the second trimester of pregnancy. It is recommended that a woman begin taking the drug on day 21-28 after childbirth (assuming she is not breastfeeding) or a second trimester abortion. If intake begins later, the woman should use additionally a barrier method of contraception during the first 7 days after the beginning of the drug Dimia® . With the resumption of sexual activity (before the beginning of taking the drug Dimia ®) pregnancy should be excluded.

Missing pills

Missing placebo pills from the last (4th) row of the blister can be ignored. However, they should be discarded to avoid inadvertently prolonging the placebo phase. The instructions below apply only to missed tablets containing the active ingredient.

If the delay in taking the pill is less than 12 hours, contraceptive protection is not reduced. A woman should take the missed pill as soon as possible (as soon as she remembers) and take the next pill at the usual time.

If the lateness is more than 12 hours, contraceptive protection may be reduced. Two basic rules can guide this:

1. Taking the pill should never be interrupted for more than 7 days.

2. 7 days of continuous pill taking is required to achieve adequate suppression of the hypothalamic-pituitary-ovarian system.

Accordingly, the following recommendations can be given to women:

Days 1-7. A woman should take the missed pill as soon as she remembers it, even if it means taking two pills at once. Then she should take the pills at the usual time. Also, for the next 7 days, a barrier method, such as a condom, should be used. If sexual intercourse occurred in the preceding 7 days, the possibility of pregnancy should be considered. The more pills skipped and the closer that skip is to the 7-day break in medication, the greater the risk of pregnancy.

Days 8-14. The woman should take the missed pill as soon as she remembers it, even if it means taking two pills at once. She should then take the pills at the usual time. If the woman has taken the pill as usual in the 7 days preceding the first missed pill, there is no need for additional contraceptive measures. However, if she missed more than 1 pill, an additional method of contraception (a barrier method, such as a condom) is needed for 7 days.

Days 15-24. The reliability of the method inevitably decreases as the placebo pill phase approaches. However, adjusting the pill regimen can still help prevent pregnancy. If one of the two regimens described below is followed, and if the woman followed the pill regimen in the preceding 7 days before skipping the pill, there will be no need for additional contraceptive measures. If this is not the case, she should follow the first of the two regimens and use additional precautions for the next 7 days.

1. The woman should take the last missed pill as soon as she remembers it, even if that means taking two pills at once. Then she should take the pills at the usual time until the active pills run out. The 4 placebo pills from the last row should not be taken, you should immediately start taking the pills from the next blister pack. It is most likely that there will be no bleeding cancellation until the end of the second package, but there may be some spotting or bleeding cancellation on the days of taking the second package.

2. A woman can also stop taking the active pills from the beginning of the pack. Instead, she should take the placebo pills from the last row for 4 days, including the days she missed the pills, and then start taking the pills from the next pack. If the woman skips the pills and does not subsequently have a bleeding discontinuation during the placebo pill phase, the possibility of pregnancy should be considered.

The use of the drug in gastrointestinal disorders

In case of severe gastrointestinal disorders (such as vomiting or diarrhea), absorption of the drug will not be complete and additional contraceptive measures will be required. If vomiting occurs within 3-4 hours of taking the active tablet, a new (replacement) tablet should be taken as soon as possible. If possible, the next tablet should be taken within 12 hours of the usual time of taking the pills. If more than 12 hours have elapsed, it is advisable to follow the instructions for skipping the pills. If the woman does not want to change her usual pattern of taking the pills, she should take an additional pill from a different package.

Delaying menstrual-like bleeding cancellation

In order to delay bleeding, a woman should skip taking the placebo pills from her starting package and start taking the drospirenone + ethinylestradiol pills from a new package. The delay can be extended until the active pills in the second package run out. During the delay, a woman may experience acyclic profuse or oozing bloody vaginal discharge. Regular use of Dimia® resumes after the placebo phase. To shift bleeding to another day of the week, it is recommended to shorten the upcoming phase of taking placebo pills by the desired number of days. When the cycle is shortened, it is more likely that the woman will not have menstrual-like withdrawal bleeding, but will have acyclic profuse or oozing vaginal bleeding when the next package is taken (just like when the cycle is lengthened).

Interaction

Note: Before taking concomitant drugs, read the instructions for use of the drug to identify potential interactions.

The effect of other drugs on the drug Dimia®. Interaction between oral contraceptives and other drugs may cause acyclic bleeding and/or contraceptive failure.

The interactions described below are reflected in the scientific literature.

The mechanism of interaction with hydantoin, barbiturates, primidone, carbamazepine and rifampicin; oxcarbazepine, topiramate, felbamate, ritonavir, griseofulvin and preparations of Hypericum perforatum is based on the ability of these active substances to induce microsomal liver enzymes. Maximum induction of microsomal liver enzymes is not achieved within 2-3 weeks, but after that it persists for at least 4 weeks after discontinuation of drug therapy.

Ineffectiveness of contraception has also been noted with antibiotics such as ampicillin and tetracycline.

The mechanism of this phenomenon is unclear. Women receiving short-term treatment (up to one week) with any of the above groups of drugs or monotherapies should temporarily use (while taking other drugs at the same time and for another 7 days after its completion) barrier methods of contraception in addition to OCs.

Women receiving rifampicin therapy, in addition to taking OCs, should use a barrier method of contraception and continue its use for 28 days after stopping treatment with rifampicin. If the concomitant medications last longer than the end of the active pills in the package, the inactive pills should be stopped and the drospirenone+ethinylestradiol pills from the next package should be started immediately.

If a woman consistently takes liver microsomal enzyme inducers, she should use other reliable, non-hormonal methods of contraception.

The major metabolites of drospirenone in the human plasma are formed without involvement of the cytochrome P450 system. Cytochrome P450 inhibitors are therefore unlikely to affect the metabolism of drospirenone.

The effect of Dimia® on other drugs. Oral contraceptives may affect the metabolism of some other active substances. Accordingly, plasma or tissue concentrations of these substances may either increase (e.g., cyclosporine) or decrease (e.g., lamotrigine). Based on in vitro inhibition and in vivo interaction studies in female volunteers taking omeprazole, simvastatin and midazolam as a substrate, the effect of drospirenone at 3 mg on the metabolism of other active agents is unlikely.

Other interactions. In patients without renal insufficiency, concomitant use of drospirenone and ACE inhibitors or NSAIDs has no significant effect on serum potassium. Nevertheless, the simultaneous use of the drug Dimia® with aldosterone antagonists or potassium-saving diuretics has not been studied. In this case, serum potassium concentration should be monitored during the first cycle of treatment.

Laboratory tests. Taking contraceptive steroids may affect the results of some laboratory tests, including determination of biochemical parameters of liver, thyroid, adrenal, and renal function, plasma protein (carrier) concentrations such as corticosteroid-binding proteins and lipid/lipoprotein fractions, carbohydrate metabolism parameters, and clotting and fibrinolysis parameters. In general, the changes remain within the range of normal values. Drospirenone causes an increase in plasma renin activity and, due to a small antimineralocorticoid activity, reduces plasma aldosterone concentration.

Special Instructions

If there are any of the conditions/risk factors mentioned below, the benefit of taking OCs should be evaluated individually for each woman and discussed with her before use. If an adverse event worsens or if any of these conditions or risk factors occur, the woman should contact her doctor. The doctor should decide if the OCs should be discontinued.

Circulatory disorders

The use of any OC increases the risk of venous thromboembolism (VTE). The increased risk of VTE is most pronounced in the first year of a woman’s use of OCs.

Epidemiological studies have shown that the incidence of VTE in women with no risk factors taking low-dose estrogen (<0.05 mg ethinylestradiol) OCs is approximately 20 per 100,000 women-years (for second-generation levonorgestrel-containing pills) or 40 per 100,000 women-years (for third-generation deogestrel/gestogen-containing pills). Women who do not use OC have 5 to 10 VTE and 60 pregnancies per 100,000 woman-years. VTE is fatal in 1-2% of cases.

The data from a large, prospective, 3-track study showed that the incidence of VTE in women with or without other risk factors for VTE who used a combination of ethinylestradiol and drospirenone, 0.03+3 mg, was consistent with the incidence of VTE in women using levonorgestrel-containing oral contraceptives and other OCs. The risk of VTE when taking Dimia® is currently unknown.

Epidemiological studies have also found an association between taking OCs and an increased risk of arterial thromboembolism (myocardial infarction, transient ischemic disturbances).

Very rarely, women taking oral contraceptives have had thrombosis of other blood vessels, such as veins and arteries of the liver, mesentery, kidneys, brain or retina. There is no consensus on the association of these events with taking hormonal contraceptives.

Symptoms of venous or arterial thrombotic/thromboembolic events or acute cerebrovascular events:

– unusual unilateral pain and/or swelling of the lower extremities;

– sudden severe chest pain, whether or not it radiates to the left arm;

– sudden shortness of breath;

– sudden onset of cough;

– any unusual severe prolonged headache;

– sudden partial or complete loss of vision;

– diplopia;

– impaired speech or aphasia;

– vertigo;

– collapse with or without partial epileptic seizures;

– weakness or very marked numbness suddenly affecting one side or one part of the body;

– movement disorders;

– acute abdomen.

Women should consult a specialist before starting to take OCs. The risk of venous thromboembolic disorders increases when taking OCs:

– with increasing age;

– hereditary predisposition (VTE has ever occurred in siblings or parents at a relatively early age);

– prolonged immobilization, extended surgery, any lower extremity surgery or major trauma. In such situations, it is recommended to discontinue the drug (in the case of elective surgery at least 4 weeks in advance) and not to resume until two weeks after full recovery of mobility. If the drug has not been discontinued beforehand, anticoagulant treatment should be considered;

– obesity (body mass index over 30);

There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in the appearance or exacerbation of venous thrombosis.

The risk of arterial thromboembolic complications or acute cerebrovascular events increases with OC use:

– with increasing age;

– smoking (women over the age of 35 are strongly advised to quit smoking if they want to take OCs);

– dyslipoproteinemia;

– arterial hypertension;

– migraine without focal neurological symptoms;

– obesity (body mass index greater than 30);

– hereditary predisposition (arterial thromboembolism ever siblings or parents at a relatively early age). If a hereditary predisposition is possible, a woman should consult a specialist before starting to take OCs;

– heart valve damage;

– atrial fibrillation.

The presence of one serious risk factor for vein disease or several risk factors for arterial disease may also be a contraindication. Anticoagulant therapy should also be considered. Women taking OCs should be properly instructed to inform their physician if symptoms of thrombosis are suspected. If thrombosis is suspected or confirmed, OCs should be discontinued. Adequate alternative contraception should be initiated because of the teratogenicity of anticoagulant therapy with indirect coumarin-derived anticoagulants.

An increased risk of thromboembolism in the postpartum period should be considered.

Other medical conditions associated with adverse vascular events include diabetes mellitus, SLE, hemolytic-uremic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis) and sickle cell anemia.

An increase in the frequency or severity of migraines while taking OCs may be an indication for immediate withdrawal.

Tumors

The most significant risk factor for cervical cancer is infection with human papillomavirus. Some epidemiological studies have reported an increased risk of cervical cancer with long-term use of OCs, but conflicting opinions remain about the extent to which these findings relate to comorbidities, such as cervical cancer screening or use of barrier methods of contraception.

A meta-analysis of 54 epidemiologic studies found a small increase in relative risk (relative risk – RR=1.24) of developing breast cancer in women who are currently taking OCs. The risk gradually declines over a 10 year period after cessation of OC use. As breast cancer rarely develops in women younger than 40 years of age, the increase in the number of breast cancers diagnosed in those using OC has little effect on the overall likelihood of breast cancer. There is insufficient evidence of a causal relationship in these studies. The increased risk may be due to an earlier diagnosis of breast cancer in OC users, to the biological effects of OC, or to a combination of both. Diagnosed breast cancer in women who have ever taken OC was clinically less severe, which is due to earlier diagnosis of the disease.

Rarely have benign liver tumors and even more rarely have malignant liver tumors in women who have taken OC. In some cases, these tumors have been life-threatening (due to intra-abdominal bleeding). This should be considered when making a differential diagnosis if there is severe abdominal pain, enlargement of the liver, or signs of intra-abdominal bleeding.

Other

The progestagen component of Dimia® is an aldosterone antagonist that retains potassium in the body. In most cases, no increase in potassium is expected. However, in a clinical study in some patients with mild to moderate renal disease who were taking potassium-containing drugs, serum potassium levels slightly increased while taking drospirenone. Therefore, it is recommended to monitor serum potassium during the first treatment cycle in patients with renal insufficiency whose serum potassium concentrations before treatment were at ICH levels and especially when concomitantly taking potassium-saving drugs. In women with hypertriglyceridemia or hereditary predisposition to it, the risk of pancreatitis may be increased when taking OCs. Although small increases in BP have been reported in many women taking OCs, clinically significant increases have been rare. Only in these rare cases is immediate discontinuation of OCs warranted. If patients with concomitant arterial hypertension have persistently elevated BP while taking OCs or if significantly elevated BP cannot be corrected with antihypertensive medications, the OCs should be discontinued. Once BP normalizes with antihypertensive medications, OCs may be restarted.

The following conditions have appeared or worsened both during pregnancy and with OC: jaundice and/or pruritus associated with cholestasis, gallstones; porphyria; SLE; hemolytic-uremic syndrome; rheumatic chorea (Sydenham’s chorea); herpes in pregnancy; otosclerosis with hearing loss. However, the evidence for their relationship to taking OCs is inconclusive.

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

Acute or chronic liver disease may be an indication to discontinue OCs until liver function normalizes. Relapse of cholestatic jaundice and/or cholestasis-related pruritus that developed during a previous pregnancy or earlier use of sex hormones are indications for discontinuation of OC.

While OCs may affect peripheral insulin resistance and glucose tolerance, regimen changes in diabetic patients taking low-hormone OCs (containing 0.05 mg ethinylestradiol) are not indicated. However, women with diabetes mellitus should be closely monitored, especially in the early stages of taking OCs.

A worsening of endogenous depression, epilepsy, Crohn’s disease, and ulcerative colitis has been observed while taking OCs.

Chloasma can occur occasionally, especially in women who already have a history of pregnancy chloasma. Women with a history of chloasma should avoid sun or UV exposure while taking OCs.

Drospirenone+ethinylestradiol coated tablets contain 48.53 mg of lactose monohydrate; placebo tablets contain 37.26 mg of anhydrous lactose per tablet. Patients with rare inherited conditions (such as galactose intolerance, lactase deficiency, or glucose-galactose absorption disorders) who follow a lactose-free diet should not take this medication.

Women who are allergic to soy lecithin may have allergic reactions.

The efficacy and safety of Dimia® as a contraceptive has been studied in women of reproductive age. It is assumed that in postpubertal period before 18 years of age the efficacy and safety of the drug are similar to those in women after 18 years of age. The use of the drug before the establishment of menarche is not indicated.

Medical examinations

Before starting or repeated use of the drug Dimia®, a complete medical history (including family history) should be taken and pregnancy should be excluded. It is necessary to measure the blood pressure, to conduct a medical examination, guided by contraindications and precautions. A woman should be reminded of the need to carefully read the instructions for use and adhere to the recommendations specified therein. The frequency and content of the examination should be based on existing practice guidelines. The frequency of medical examinations is individual for each woman, but should be at least once every 6 months.

A woman should be reminded that oral contraceptives do not protect against HIV infection (AIDS) or other sexually transmitted diseases.

The effectiveness of OCs may decrease if, for example, you skip taking drospirenone + ethinylestradiol tablets, have gastrointestinal distress while taking drospirenone + ethinylestradiol tablets, or are taking other medications at the same time.

Inadequate cycle control

As with other OCs, women may experience acyclic bleeding (masturbation or bleeding withdrawal), especially in the first months of use. Consequently, any irregular bleeding should be evaluated after a three-month adaptation period.

If acyclic bleeding recurs or begins after several regular cycles, the possibility of non-hormonal disorders should be considered and measures should be taken to rule out pregnancy or cancer, including a therapeutic and diagnostic cervical curettage. Some women do not experience bleeding withdrawal during the placebo phase. If OCs were taken according to the instructions for use, it is unlikely that the woman is pregnant. However, if the rules of intake were violated before the first missed menstrual withdrawal bleeding or two bleeding missed, pregnancy should be ruled out before continuing to take OCs.

The effect on the ability to drive vehicles and mechanisms. No effect has been detected.

Features

Drospirenone

Intake. When taken orally drospirenone is quickly and almost completely absorbed in the gastrointestinal tract. Cmax of drospirenone in the serum is about 38 ng/mL and is reached about 1-2 hours after a single dose. Bioavailability is 76-85%. Concomitant intake with food does not affect the bioavailability of drospirenone.

Distribution. After oral administration, plasma concentration of drospirenone decreases with a final T1/2 of 31 h. Drospirenone binds to serum albumin and does not bind to sex hormone-binding globulin (hSPH) or corticosteroid-binding globulin (transcortin). Only 3-5% of the total serum concentration of drospirenone exists as free steroids. Ethinylestradiol-induced increases in hGH do not affect the binding of drospirenone to serum proteins. The mean apparent Vd of drospirenone is (3.7±1.2) L/kg.

Metabolism. Drospirenone is actively metabolized after oral administration. The main metabolites in blood plasma are the acidic forms of drospirenone, formed when the lactone ring opens, and 4,5-dihydro-drospirenone-3-sulfate, which are formed without the participation of the P450 system. Drospirenone is metabolized to a small extent by cytochrome P450 3A4 and is able to inhibit this enzyme as well as cytochromes P450 1A1, P450 2C9 and P450 2C19 in vitro.

Elimination. Renal clearance of drospirenone metabolites in serum is (1.5±0.2) ml/min/kg. Drospirenone is excreted only in trace amounts unchanged. Drospirenone metabolites are excreted by the kidneys and through the intestine with an excretion ratio of about 1.2:1.4. T1/2 metabolites by the kidneys and through the intestine is about 40 h.

Css. During the treatment cycle, the maximum Css of drospirenone in plasma is about 70 ng/mL, reached after 8 days of treatment. Serum concentrations of drospirenone increase about 3-fold due to the ratio of the final T1/2 to the dosing interval.

Ethinylestradiol

Introduction. When taken orally, ethinylestradiol is absorbed quickly and completely. Cmax in blood serum is about 33 pkg/ml and is reached within 1-2 hours after a single oral administration. Absolute bioavailability due to presystemic conjugation and presystemic metabolism is approximately 60%. Concomitant ingestion decreased the bioavailability of ethinylestradiol in approximately 25% of the patients studied; there was no change in others.

Distribution. Serum concentrations of ethinylestradiol decrease biphasically, with a final distribution phase T1/2 of approximately 24 h. Ethinylestradiol binds well but nonspecifically to serum albumin (approximately 98.5%) and induces increased serum concentrations of hGH. Vd is about 5 L/kg.

Metabolism. Ethinylestradiol is a substrate of presystemic conjugation in the mucosa of the small intestine and in the liver. Ethinylestradiol is primarily metabolized by aromatic hydroxylation, producing a wide range of hydroxylated and methylated metabolites, which are present both in free form and as conjugates with glucuronic acid. Renal clearance of ethinylestradiol metabolites is approximately 5 ml/min/kg.

Evacuation. Unchanged ethinylestradiol is practically not excreted from the body. Metabolites of ethinylestradiol are excreted by the kidneys and through the intestine at a ratio of 4:6. T1/2 metabolites is about 24 h.

Css. It occurs in the second half of the treatment cycle, and the serum concentration of ethinylestradiol increases 2-2.3-fold.

Particular patient groups

In impaired renal function. Css of drospirenone in plasma in women with mild renal insufficiency (creatinine Cl – 50-80 ml/min) was comparable to corresponding values in women with normal renal function (creatinine Cl – >80 ml/min). In women with moderate renal insufficiency (creatinine Cl from 30 ml/min to 50 ml/min) the plasma concentration of drospirenone was on average 37% higher than in women with normal renal function. Drospirenone was well tolerated in all groups. Drospirenone administration had no clinically significant effect on serum potassium. Pharmacokinetics in severe renal failure have not been studied.

In case of liver dysfunction. Drospirenone is well tolerated in patients with mild to moderate hepatic impairment (Child-Pugh class B). Pharmacokinetics in severe hepatic impairment have not been studied.

Contraindications

Dimia, like other OCs, is contraindicated for any of the following conditions:

Side effects

Overdose

There have been no cases of overdose of Dimia® so far.

Based on the general experience of using OCs the potential symptoms of overdose may be: nausea, vomiting, slightly pronounced bleeding from the vagina.

Treatment: there are no antidotes. Further treatment should be symptomatic.

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