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Ethinyl Estradiol/Folic Acid/Levonorgestrel Review

Ethinyl Estradiol/Folic Acid/Levonorgestrel is an oral contraceptive which is taken daily to prevent pregnancy.


Indications for use

  • Pregnancy prevention.

Mechanism of action

The contraceptive effect of this drug is based on the interaction of various mechanisms, including the suppression of ovulation and changes in the endometrium and cervical mucus.

Dosage and mode of application

Tablets should be taken in the order indicated on the blister pack, every day at about the same time.

Take one tablet daily for 28 consecutive days. Each subsequent pack should be started without interruption. Withdrawal bleeding usually starts 2-3 days after taking the last inert pill and may not end when you start taking pills from the next pack.

If you take the drug for the first time:

Start taking tablets on the first day of your menstruation. You may also start taking pills on day 2–5 of your period, but in this case it is recommended to use additional non-hormonal methods of contraception for the first 7 days (the first cycle of the drug).

If you have previously used another combination hormonal contraceptive (COC, vaginal ring or transdermal patch):

Start taking tablets the next day after taking the last pill from the previous pack. If you are switching from a vaginal ring or transdermal patch, start taking tablets immediately after removing the vaginal ring or transdermal patch, but no later than the next day after removing the vaginal ring or transdermal patch.

If you have previously used contraceptives containing only gestogen (mini-pills, injections, implant):

You can switch from birth control pills on any day, from injections – on the day when the next injection is due, from the implant – on the day it is removed.

Use after abortion:

Tablets can be taken immediately. Additional contraceptive measures are not required.

Use after childbirth and after abortion in the second trimester of pregnancy:

The pack can be started 21-28 days after childbirth or abortion in the second trimester. If use is started later, it is necessary to use an additional back-up method of contraception during the first 7 days of taking pills.

Use in gastrointestinal disorders:

If vomiting or severe diarrhea occurs within 3–4 hours after taking the pill, the pill may not be completely absorbed. In this case, you must re-take tablet Leverett mini.

Delaying your period with birth control pills:

In order to delay menstruation after the completion of the previous 21-day cycle package, you should immediately continue to take tablets from a new package without a break. If you used a 28-day cycle pack, discard inert tablets and start taking tablets from a new pack. Spotting may occur. Once you’ve finished the second pack, resume taking tablets from the next pack in your usual order.

If you want your menstrual cycle to begin on another day of the week, the duration of the interruption in hormones can be shortened as needed. However, the shorter the interval, the higher the likelihood of spotting during the use of the second pack.


  • Symptoms: nausea, vomiting, dizziness, abdominal pain, drowsiness, fatigue, tenderness of the mammary glands, menstrual bleeding (in young females);
  • Treatment: symptomatic.

Side effects

Ethinyl Estradiol/Folic Acid/Levonorgestrel can cause the following side effects:

  • headache;
  • migraine;
  • nausea, vomiting, abdominal pain;
  • decreased libido;
  • acne;
  • violation of the menstrual cycle, dysmenorrhea, amenorrhea;
  • increase or decrease in body weight;
  • depressed state, mood swings;
  • breast tenderness, breast enlargement;
  • discharge from the mammary glands;
  • pain in the chest;
  • bleeding, bleeding;
  • fluid retention;
  • abdominal pain, flatulence;
  • chloasma;
  • alopecia;
  • hirsutism;
  • arterial hypertension;
  • hypertriglyceridemia;
  • rash, urticaria;
  • vaginitis, candidiasis;
  • increase or decrease in appetite;
  • impaired glucose tolerance;
  • allergic reactions, urticaria, angioedema;
  • increased sensitivity;
  • intolerance to contact lenses;
  • cholestatic jaundice;
  • decrease in the concentration of folic acid in the blood plasma;
  • erythema nodular;
  • hepatocellular carcinoma;
  • erythema multiforme;
  • neuritis;
  • retinal thrombosis;
  • exacerbation of varicose veins;
  • pancreatitis with concurrent severe hypertriglyceridemia;
  • ischemic colitis;
  • hepatitis, hepatic dysfunction;
  • hemolytic uremic syndrome;
  • herpes pregnant;
  • otosclerosis;
  • exacerbation of systemic lupus erythematosus;
  • exacerbation of porphyria;
  • exacerbation of Sideyama’s chorea;
  • exacerbation of depression;
  • inflammatory bowel disease (Crohn’s disease or ulcerative colitis).


Do not use Ethinyl Estradiol/Folic Acid/Levonorgestrel if you have any of the following conditions:

  • venous thromboembolism or its history (for example, deep vein thrombosis, pulmonary thromboembolism) in combination with risk factors or without them;
  • arterial thromboembolism or its history, in particular, myocardial infarction, transient ischemic attack, angina pectoris and cerebrovascular accident;
  • serious or multiple risk factors for venous or arterial thrombosis;
  • migraine with focal neurological symptoms;
  • increased sensitivity to the active substance or to any of the excipients;
  • a history of thrombosis precursors (transient cerebral circulation or angina);
  • a stroke or its history;
  • severe arterial hypertension;
  • hereditary or acquired susceptibility to venous thromboembolism (resistance to activated protein C (including Leiden factor V), deficiency of antithrombin III, protein C or protein S);
  • smoking;
  • diagnosed or suspected hormone-dependent malignant tumors of the breast and genital organs;
  • cerebrovascular disorders or their history;
  • diabetes with manifestations of micro – or macroangiopathy;
  • serious liver diseases or their presence in history (before normalization of the functional “liver” tests);
  • liver tumors or their presence in history (benign or malignant);
  • pancreatitis associated with severe hypertriglyceridemia or its history;
  • vaginal bleeding of unknown etiology;
  • amenorrhea of unknown etiology;
  • pregnancy and lactation;
  • hereditary fructose intolerance, deficiency of the enzyme Lapp-lactose, malabsorption of glucose-galactose;
  • children up to 18 years.


Medicines that may affect the effects of COC:

In order to identify potential drug interactions, you should always study the information on the use of any concomitant drugs!

Drug interactions that lead to increased clearance of sex hormones can cause breakthrough bleeding and ineffective contraceptive protection. This effect has been detected in hydantoins (for example, phenytoin), barbiturates, primidone, carbamazepine and rifampicin. There are also suggestions regarding oxcarbazepine, topiramate, felbamate, griseofulvin, ritonavir, nevirapine, and preparations containing St. John’s wort. The mechanism of their action is probably based on the ability of these substances to increase the activity of “liver” enzymes. The maximum induction of enzymes, as a rule, is observed not earlier than 2-3 weeks after the start of use of these drugs but can persist for at least 4 weeks after their cancellation. Cases of the ineffectiveness of contraceptives have also been detected with the simultaneous use of antibiotics (for example, ampicillin tetracycline).

In the case of short-term use of any of these drugs, causing an increase in the activity of “liver” enzymes, it is recommended to use additional barrier methods of contraception from the moment you start taking these drugs, during the entire period of treatment and for 4 weeks after their withdrawal. Women who take these short-course antibiotics should temporarily use back-up methods of contraception during the concomitant use and for 7 days after discontinuation. If the next pack of the contraceptive is finished earlier than the period that requires the use of additional contraceptives, you should start taking active tablets from the next package without using placebo tablets.

In the case of long-term use of these drugs, women are recommended to use other contraceptives.

Drug interactions that increase the concentration of sex hormones can increase the frequency and severity of side effects. The following agents increase the concentration of sex hormones: agents that inhibit sulfonation of ethinyl estradiol in the gastrointestinal tract (for example, ascorbic acid or paracetamol), atorvastatin (an increase in the concentration of ethinyl estradiol by 20%), inhibitors of microsomal liver enzymes, such as imidazole, antifungal drugs (for example, fluconazole), indinavir, troleandomycin.

Effects of COC on other drugs:

Sex steroid hormones can increase plasma concentrations of cyclosporine, diazepam (and some other benzodiazepines), theophylline, glucocorticoids, which can lead to the development of toxic effects. Plasma concentration of clofibrate, paracetamol, morphine, lorazepam (and some other benzodiazepines) is reduced. Simultaneous intake of lamotrigine and COC can lead to a decrease in the plasma concentration of lamotrigine and impairment of the control of convulsive seizures in women who have started using COC.

The need for insulin or oral hypoglycemic drugs can be altered by affecting glucose tolerance.

Trolandomitsin may increase the risk of cholestasis when used together with COC.

Pregnancy and breastfeeding

Birth control pills are not used during pregnancy. There is little data about how COCs can affect the fetus.

Do not use this drug if you are breastfeeding since sex hormones can change breast milk production and composition. There is little data about how COCs can affect the baby.

What if I miss a pill?

If the missed tablet is taken within 12 hours, no additional precautions are required; the missed tablet should be taken as soon as possible, and the following tablets should be taken at the usual time.

If the delay between doses exceeds 12 hours, birth control will be reduced. In this case, the following rules should apply:

  • you should not stop taking pills for more than 7 days;
  • for proper suppression of the hypothalamus system – pituitary – ovarian, tablets should be taken within 7 days without a break.

Based on this, the following guidelines should be followed:

You miss a tablet on Week 1:

You need to take the missed pill as soon as possible, as soon as you remember (even if it means taking two pills at the same time). The next pill is taken at the usual time. Additionally, you should use a back-up method of contraception (for example, a condom) during the next 7 days. If you had sexual intercourse within a week before the pill was missed, the likelihood of pregnancy must be considered. The more pills are missed and the closer they are to the phase of inert tablets, the greater the likelihood of pregnancy.

You miss a tablet on Week 2:

You need to take the missed pill as soon as possible, as soon as you remember (even if it means taking two pills at the same time). The next pill is taken at the usual time. If the pills were taken correctly within the 7 days preceding the missed pill, there is no need for additional contraceptive measures. Otherwise, as well as when missing two or more pills, you must additionally use back-up methods of contraception (for example, a condom) during the next 7 days.

You miss a tablet on Week 3:

The risk of reducing the contraceptive reliability is inevitable due to the upcoming break in taking active pills. You must strictly adhere to one of the following two options. Moreover, if all pills were taken correctly within the 7 days preceding the first missed pill, there is no need to use additional contraceptive methods.

  1. You need to take the last missed pill as soon as possible (even if it means taking two pills at the same time). Then keep taking 1 tablet per day until the pack is empty. The next pack should start immediately. Withdrawal bleeding is unlikely t occur until the second pack is finished but you may have spotting while taking the pills;
  2. You can also stop taking the pills from the current pack, take a break for 7 days, including the day of missing the pill and then start taking pills from a new pack.

If you have no withdrawal bleeding after missing active pills, you must exclude pregnancy.

If you miss any of the inert tablets, discard them and keep taking 1 tablet per day until you finish the pack. Additional birth control is not required.


Before taking Ethinyl Estradiol/Folic Acid/Levonorgestrel, it is necessary to conduct a full medical examination, exclude pregnancy and malignant neoplasms. With prolonged use, catch-up examinations should be carried out at least 1 time per year.

Venous and arterial thromboembolism 

Women taking COCs have a higher risk of venous and/or arterial thromboembolic complications (especially with risk factors).

If you suspect or confirm venous thromboembolism (VTE) or arterial thromboembolism (ATE), you should stop taking COC.

If you have risk factors, the potential risk and expected benefits of hormonal contraception should be carefully evaluated before taking the drug.

Risk factors:

  • a family history of venous or arterial thromboembolism at a relatively early age;
  • heart and kidney disease;
  • a migraine, in particular with focal neurological symptoms;
  • valvular disease;
  • atrial fibrillation;
  • surface phlebitis, pronounced tendency to varicose veins, peripheral circulatory disorders;
  • increased blood pressure (above 140/190 mm Hg);
  • dyslipoproteinemia. Levonorgestrel, a component of the drug, can lead to an increase in low-density lipoprotein. If necessary, doses of lipid-lowering therapy should be adjusted. In patients with dyslipoproteinemia, ethinyl estradiol can lead to a significant increase in plasma triglycerides, and in some cases the risk of pancreatitis increases. In women with uncontrolled dyslipoproteinemia, alternative methods of contraception should be considered;
  • sickle cell anemia;
  • liver diseases;
  • gallbladder disease;
  • depression. It is necessary to clarify whether depression is associated with the use of sex hormones. If necessary, use other non-hormonal methods of contraception;
  • decreased glucose tolerance/diabetes mellitus. Although COCs may influence insulin resistance and glucose tolerance, there is no need to change the therapeutic regimen in diabetic patients using low-dose combined oral contraceptives. However, women with diabetes should be carefully monitored while taking COCs;
  • smoking (the risk is especially high in smoking women over the age of 35;
  • epilepsy (in case of an increase in epileptic seizures while taking birth control pills, other methods of contraception should be considered);
  • chorea;
  • chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis);
  • hemolytic uremic syndrome;
  • systemic lupus erythematosus;
  • uterine fibroids;
  • otosclerosis;
  • age over 40;
  • obesity (body mass index more than 30 kg / m2);
  • prolonged bed rest, major surgery, any surgery on the legs or significant injury. In this case, it is recommended to discontinue using birth control pills in advance, at least four weeks before the operation or prolonged bed rest, and not to resume the use within two weeks after the end of bed rest. Temporary immobilization, including flights on an airplane lasting more than 4 hours, may increase the risk of developing VTE, in particular in women having other risk factors;
  • postpartum period.

The risk of thrombosis and thromboembolism during pregnancy is higher than when taking low-dose COC.

The use of any COC increases the risk of developing VTE in female patients, compared with women who do not use them.

Preparations containing levonorgestrel have the lowest risk of developing VTE.

Venous thromboembolism can be fatal in 1-2% of cases.

Symptoms of venous thrombosis: unilateral swelling in the leg, pain or discomfort in the leg only in the upright position or when walking, a temperature increase in the affected limb, redness or discoloration of the skin on the leg.

Symptoms of pulmonary embolism: sudden onset of unexplained dyspnea or rapid breathing, sudden attack of cough, which may be accompanied by hemoptysis, acute chest pain, which may increase with deep breathing, severe dizziness, rapid or irregular heartbeat. Some of these symptoms (coughing and shortness of breath) are nonspecific and therefore may be mistakenly interpreted as signs of more frequent and less severe disorders (respiratory tract infections).

Other signs of vascular occlusion may include sudden pain, swelling, and blue limb.

Sometimes a sudden loss of vision can occur.

Symptoms of arterial thrombosis

Cerebrovascular disorders: sudden weakness or numbness of the face, upper and lower extremities, especially on one side of the body, sudden gait disturbance, dizziness, loss of balance or coordination of movements, sudden confusion, speech or difficulty in perception, sudden deterioration of one or both eyes, sudden severe or prolonged headache for no apparent reason, loss of consciousness. Other signs of vascular occlusion: sudden pain, swelling or weak cyanosis of the extremities, symptoms of an acute abdomen.

Symptoms of myocardial infarction: pain, discomfort, pressure, heaviness, a feeling of compression or distension in the chest, arm or behind the sternum, discomfort with irradiation in the back, cheekbones, larynx, arm, stomach, fullness and distention in the stomach, feeling of suffocation sweating, nausea, vomiting, dizziness, severe weakness, anxiety, shortness of breath, rapid or irregular heartbeat.

Women taking combination oral contraceptives should consult a doctor immediately if they have signs of thrombosis.

Circulatory disorders can also occur in malignant neoplasms, diabetes mellitus, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis), and sickle cell anemia.


There are reports of some increase in the risk of cervical cancer with long-term use of COCs, but there is conflicting evidence on the extent to which this may be due to other factors, including sexual behavior, the use of back-up methods of contraception and the human papillomavirus (HPV).

There is a slightly increased relative risk of breast cancer diagnosed in women who are using COCs. The increased risk gradually disappears within 10 years after discontinuation of these drugs. Due to the fact that breast cancer is rarely observed in women younger than 40 years old, an increase in the number of breast cancer diagnoses in women who are currently taking or using COCs recently is insignificant relative to the overall risk of developing the disease. Its association with COC is not proven. Women who have used COC have a clinically less pronounced risk of breast cancer than women who have never used such drugs.

In rare cases, COC may cause benign liver tumors and (in very rare cases) – malignant tumors.

Other diseases

There are reports of cases of increased blood pressure caused by COC, especially with prolonged use and in older women. Women with hypertension in history or in the presence of kidney disease should consider other methods of contraception.

In women with hereditary angioedema, exogenous estrogens can provoke or aggravate the symptoms of this disease.

Women with a tendency to chloasma, especially in the history of pregnancy, should avoid prolonged exposure to the sun and exposure to ultraviolet radiation.

Effect on the menstrual period

During the first months of use, irregular bleeding/spotting may occur. Therefore, the assessment of any irregular bleeding should be carried out only after a period of adaptation of approximately three cycles.

If irregular bleeding recurs or develops after previous regular cycles, a thorough examination should be performed to rule out malignant tumors or pregnancy.

Some women may not develop withdrawal bleeding when taking inert tablets. If the drug was taken as directed, it is unlikely that the woman is pregnant. However, if COC has been taken irregularly or if a woman misses two withdrawal bleedings in a row, pregnancy should be excluded.

After discontinuing COCs, it may take some time before a normal cycle is established. Some women may have amenorrhea or oligomenorrhea (possibly with anovulation), if menstrual irregularities have occurred before.

Reduced efficiency

The effectiveness of COCs can be reduced by missing pills, vomiting and diarrhea or as a result of drug interactions.


The drug contains lactose. Patients with rare hereditary disorders, such as galactose intolerance, deficiency of the enzyme Lapp-lactase, glucose-galactose malabsorption, who are on a lactose-free diet, should take into account the amount of lactose in the preparation.

Ethinyl Estradiol/Folic Acid/Levonorgestrel does not protect against HIV infection (AIDS) and sexually transmitted diseases!

Laboratory research

Contraceptive steroid hormones may affect the results of some laboratory tests, including biochemical indicators of the liver, thyroid, adrenal and kidney function, concentration of plasma transport proteins (corticosteroid-binding globulin, lipid/lipoprotein fractions), carbohydrate metabolism, coagulation and fibrin metabolism. The observed changes usually remain within the reference values.

Effect of the drug on the ability to drive a vehicle or operate potentially dangerous machinery

The drug does not affect or has an insignificant effect on the ability to drive vehicles and work with potentially dangerous machinery.

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