Instructions for use REGULON® (REGULON®)

Regulon

If any of the following conditions/diseases/risk factors are present, a careful assessment of the benefit-risk ratio of using COCs should be carried out. This issue should be discussed with the woman before starting the drug. In case of exacerbation of diseases, deterioration of condition, or the appearance of the first symptoms of conditions/diseases or risk factors, a woman should immediately consult a doctor to decide whether to stop taking the drug.

Risk of developing VTE and ATE

Epidemiological studies have established an association between the use of COCs and an increased risk of arterial and venous thrombosis and thromboembolism, such as myocardial infarction, stroke, DVT and PE. These diseases are extremely rare.

The use of any COC is associated with an increased risk of developing VTE, manifested as DVT and/or PE. The greatest risk of developing VTE is observed in the first year of COC use. An increased risk of developing this complication is also observed when COC use is resumed after a break of 4 weeks or more.

Some epidemiological studies suggest that women taking low-dose COCs containing third-generation progestogens, including desogestrel, have an increased risk of developing VTE compared with women taking drugs containing the progestogen levonorgestrel, norgestimate or norethisterone. These studies demonstrated an approximately twofold increase in the risk of developing VTE.

The annual incidence of VTE in women taking COCs containing desogestrel ranges from 9 to 12 cases per 10,000 women; in women who do not use COCs, the incidence of VTE is 2 cases per 10,000 women. The incidence of VTE with COC use is lower than the incidence of VTE during pregnancy (up to 20 cases per 10,000 women) and the postpartum period (40 to 65 cases per 10,000 women). VTE can be fatal in 1-2% of cases.

It is extremely rare that when taking COCs, thrombosis occurs in other blood vessels (for example, in the veins and arteries of the liver, mesentery, kidneys, brain or retina).

Symptoms of VTE and ATE may include

: sudden pain and/or swelling of the lower extremity, sudden intense chest pain, with or without radiation to the left arm, sudden shortness of breath, sudden cough, unusual severe and prolonged headache, sudden partial or complete loss of vision, diplopia, speech impairment or aphasia , dizziness, collapse with or without a convulsive attack, weakness or severe numbness that suddenly appears on one side of the body, movement disorders, “acute abdomen.”

The risk of developing VTE increases with the presence of the following risk factors:

- age;

— obesity (BMI more than 30 kg/m2);

- a family history of venous or arterial thrombosis, or thromboembolism in brothers, sisters or parents under the age of 50 years (if a hereditary predisposition is suspected, you should consult a specialist before starting to take COCs);

- prolonged immobilization, major surgery, any operation on the lower extremities or pelvis, neurosurgery, major trauma. In these cases, you should stop taking the COC (at least 4 weeks before planned surgery) and resume it only 2 weeks after the woman has fully recovered her mobility;

— temporary immobilization, including air travel lasting more than 4 hours, is also a factor in the development of VTE, especially in women with other risk factors. The possible role of varicose veins and superficial thrombophlebitis in the development of VTE remains controversial.

The risk of developing ATE increases with the presence of the following risk factors:

- age;

- smoking (the risk increases to a greater extent in women over 35 years of age);

- dislipoproteinemia;

— obesity (BMI more than 30 kg/m2);

- arterial hypertension;

- migraine;

- heart valve disease;

- atrial fibrillation;

- a family history of venous or arterial thrombosis, or thromboembolism in brothers, sisters or parents under the age of 50 years (if a hereditary predisposition is suspected, you should consult a specialist before starting to take COCs).

It is necessary to take into account the increased risk of thromboembolism in the postpartum period.

Other conditions/diseases in which circulatory disorders are observed:

diabetes mellitus, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease (eg, Crohn's disease or ulcerative colitis) and sickle cell anemia.

An increase in the frequency or intensity of migraine (may be a prodromal symptom of cerebrovascular accident) while taking a COC is grounds for immediate discontinuation of its use.

Biochemical factors that may indicate hereditary or acquired predisposition to VTE or ATE include activated protein C resistance, hyperhomocysteinemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).

When assessing the benefit/risk ratio, it should be taken into account that therapy for these conditions/diseases can reduce the associated risk of thrombosis.

Tumors

The most important risk factor for the development of cervical cancer (CC) is persistent human papillomavirus (HPV) infection. Epidemiological studies show an increased risk of developing cervical cancer in women infected with HPV and long-term users of COCs (> 5 years), however, there are still contradictions regarding the degree of influence of various factors on these data, in particular cervical screening examinations or characteristics of a woman’s sexual behavior (number of sexual partners and the use of barrier methods of contraception), as well as the cause-and-effect relationship of these factors.

A meta-analysis of the results of 54 epidemiological studies revealed a slight increase (1.24) in the risk of developing breast cancer (BC) in women using COCs. The increased risk gradually decreases over 10 years after discontinuation of COCs. Due to the fact that breast cancer is rare in women under 40 years of age, the increase in the incidence of breast cancer in women who are currently taking COCs or have recently taken it is insignificant in relation to the overall risk of developing this disease. Its connection with COC use has not been proven. The observed increase in risk may also be a consequence of earlier diagnosis of breast cancer in women taking COCs (they are diagnosed with earlier clinical forms of breast cancer than women not taking COCs), the biological effects of COCs, or a combination of both of these factors.

Very rarely, when using COCs, cases of the development of benign, and even more rarely, malignant liver tumors were observed. In some cases, these tumors have resulted in life-threatening intra-abdominal bleeding. In case of severe abdominal pain, liver enlargement or signs of intra-abdominal bleeding, this should be taken into account when making a differential diagnosis.

Other states

— Depressed mood and depression are known adverse reactions when using hormonal contraceptives (see section “Side effects”). Depression can be a serious disorder and is a known risk factor for suicidal behavior and suicide. Women should be advised to contact their doctor if mood changes or depressive symptoms occur, including soon after starting treatment.

- Women with hypertriglyceridemia or a corresponding family history have an increased risk of developing pancreatitis when taking COCs.

- Many women taking COCs experienced a slight increase in blood pressure, but clinically significant increases in blood pressure were rare. The connection between taking COCs and arterial hypertension has not been established. However, if persistent arterial hypertension develops while taking COCs, then it is advisable to stop taking COCs and prescribe antihypertensive therapy. If blood pressure is adequately controlled with antihypertensive drugs, it is possible to resume taking COCs.

— During pregnancy and during the use of COCs, the development or worsening of the following conditions was noted, although their relationship with the use of contraceptives has not been definitively established: jaundice and/or itching caused by cholestasis, formation of gallstones, porphyria, systemic lupus erythematosus, hemolytic uremic syndrome, Sydenham's chorea (minor chorea), gestational herpes, hearing loss due to otosclerosis, hereditary angioedema.

— Acute or chronic liver dysfunction may warrant discontinuation of COCs until liver function tests return to normal. Recurrence of cholestatic jaundice, previously observed during pregnancy or when using sex hormones, requires discontinuation of COCs.

— Despite the fact that COCs can have an effect on insulin resistance and glucose tolerance, there is usually no need to adjust the dose of hypoglycemic drugs in patients with diabetes mellitus taking COCs. However, patients with diabetes mellitus should be under close medical supervision while taking COCs.

- Worsening of endogenous depression, epilepsy, Crohn's disease and ulcerative colitis has been reported with the use of COCs.

- Sometimes, when taking COCs, pigmentation of the facial skin (chloasma) may occur, especially if it occurred earlier during pregnancy. Women with a predisposition to chloasma should avoid direct sunlight and ultraviolet radiation from other sources when taking COCs.

— 1 tablet of Regulon contains 67.66 mg of lactose monohydrate. The drug is contraindicated for women with rare hereditary diseases associated with lactase deficiency, lactose intolerance, glucose-galactose malabsorption, and those on a lactose-free diet.

All of the above information should be taken into account when choosing a contraceptive method.

Medical examinations/consultations

Instructions for use REGULON® (REGULON®)

If any of the following conditions or risk factors are present, the rationale for using Regulon® should be discussed with the woman.

If these conditions or risk factors worsen or occur, the woman is advised to contact her doctor and discuss with him the possibility of stopping taking Regulon®.

Circulatory disorders

Risk of venous thromboembolic complications (VTE)

The use of combined hormonal contraceptives increases the risk of venous thromboembolic complications (VTE) in patients taking them compared to those not taking these drugs.

Drugs containing levonorgestrel, norgestimate, or norethisterone are associated with the lowest risk of VTE. Other drugs, such as Regulon®, may double the risk of VTE. The decision to use a drug that is not one of the drugs with the lowest risk of VTE should be made only after a conversation with the woman. It is necessary to ensure that she understands the risk of VTE while taking Regulon®, as well as the impact of her existing risk factors on it, and that the greatest risk of developing VTE is observed in the first year of using the drug. In addition, there is evidence that the risk increases when combined hormonal contraceptives are resumed after a break of 4 weeks or more.

Approximately 2 out of 10,000 women who are not pregnant and not taking combined hormonal contraceptives develop VTE over the course of a year. However, a woman's individual risk may be much higher given her risk factors (see below).

It is estimated1 that out of 10,000 women using combined hormonal contraceptives containing desogestrel, 9-12 will develop VTE within a year (compared with approximately 62 cases among women using levonorgestrel-containing combined hormonal contraceptives).

In both cases, the number of VTEs per year is less than the number expected during pregnancy or the postpartum period.

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

In very rare cases, thrombosis of other vessels (for example, hepatic, mesenteric, renal or retinal veins and arteries) has been reported in patients taking combined hormonal contraceptives.

1 These incidence rates were derived from a pooled analysis of data from epidemiological studies using relative risks for different drugs compared with those for combined hormonal contraceptives containing levonorgestrel.

2 The median range of 5–7 per 10,000 woman-years, based on the relative risk for combined hormonal contraceptives containing levonorgestrel compared with no use, is approximately 2.3–3.6.

Risk factors for the development of venous thromboembolic complications (VTE)

The risk of developing venous thromboembolic complications when using combined hormonal contraceptives may be significantly increased in women with additional risk factors, in particular, with multiple risk factors (see table).

Regulon® is contraindicated in women with multiple risk factors that place her at high risk of developing venous thrombosis. If a woman has more than one risk factor, a situation may arise in which the risk increases to a greater extent than with a simple summation of individual factors:

• in this case, the overall risk of developing VTE should be taken into account. If the benefit/risk ratio is unfavorable when assessed, combined hormonal contraceptives should be discontinued.

Table. Risk factors for the development of venous thromboembolic complications (VTE)

There is no consensus on the possible role of varicose veins and superficial vein thrombophlebitis in the development or progression of venous thrombosis.

The increased risk of thromboembolism during pregnancy and especially in the first 6 weeks of the postpartum period should be taken into account.

Symptoms of venous thromboembolic complications (VTE)

Women should be informed that if symptoms occur, they should seek emergency medical attention and tell their health care provider that they are using a combined hormonal contraceptive.

Symptoms of deep vein thrombosis (DVT) may include:

• unilateral swelling of the lower limb and/or feet, or swelling along the vein of the lower limb;
• pain or tenderness in the lower extremity that is felt when standing or while walking;
• increased temperature of the affected lower limb; redness of the skin or change in skin color of the lower limb.

Symptoms of pulmonary embolism (PE) may include:

• sudden onset of causeless shortness of breath or rapid breathing;
• sudden cough for no obvious reason, possibly with blood;
• sharp chest pain;
• lightheadedness or dizziness;
• fast or irregular heartbeat.

Some of the symptoms reported (eg, shortness of breath, cough) are nonspecific and may be mistaken for more common or less severe illnesses (eg, respiratory tract infections).

Other signs of blocked blood vessels may include sudden pain, swelling, and mild blueness of the limb.

In the case of ocular embolism, symptoms can range from blurred vision (without pain) to (as it progresses) loss of vision. In some cases, complete loss of vision can develop almost immediately.

Risk of developing arterial thromboembolic complications (ATE)

The results of epidemiological studies have linked the use of combined hormonal contraceptives with an increased risk of arterial thromboembolic complications (myocardial infarction) or cerebrovascular accidents (for example, transient cerebrovascular accident, stroke). Cases of arterial thromboembolism can be fatal.

Risk factors for the development of arterial thromboembolic complications (ATE)

The risk of developing arterial thromboembolic complications or cerebrovascular accidents when using combined hormonal contraceptives increases in women with risk factors (see table). Regulon® is contraindicated in women with one serious risk factor or multiple risk factors for the development of ATE, which place her at high risk of developing arterial thromboembolism. If a woman has more than one risk factor, a situation may arise in which the risk increases to a greater extent than with a simple summation of individual factors:

• in such a case the overall risk must be taken into account. If the benefit/risk ratio is unfavorable when assessed, combined hormonal contraceptives should be discontinued.

Table. Risk factors for the development of arterial thromboembolic complications (ATE)

Symptoms of arterial thromboembolic complications (ATE)

Women should be informed that if symptoms occur, they should seek emergency medical attention and tell their health care provider that they are using a combined hormonal contraceptive.

Symptoms of a cerebrovascular accident may include:

• sudden weakness or numbness of the face, arm, or leg, especially on one side of the body;
• sudden difficulty walking, dizziness, loss of balance or coordination;
• sudden confusion, difficulty speaking or understanding;
• sudden loss of vision in one or both eyes;
• sudden, severe or prolonged headache without known cause;
• loss of consciousness or fainting with or without convulsions.

The temporary nature of symptoms suggests a transient ischemic attack (TIA).

Symptoms of myocardial infarction (MI) may include:

• pain, discomfort, pressure, heaviness, a feeling of tightness or fullness in the chest, arm or chest;
• discomfort radiating to the back, lower jaw, throat, arm, stomach;
• feeling of fullness, indigestion, or suffocation;
• sweating, nausea, vomiting, or dizziness;
• extreme weakness, anxiety, or shortness of breath;
• fast or irregular heartbeat.

Tumors

Epidemiological studies indicate that long-term use of oral contraceptives is a risk factor for the development of cervical cancer in women infected with human papillomavirus (HPV). However, there is still no consensus on the extent to which the data are susceptible to bias (for example, differences in the number of sexual partners or the use of barrier contraceptive methods).

According to the results of a meta-analysis of 54 international studies, women taking combined oral contraceptives have a slightly increased relative risk of developing breast cancer (RR = 1.24). Over the course of 10 years after stopping combined hormonal contraceptives, the additional risk gradually disappears. Because breast cancer is rare in women under 40 years of age, the additional number of cases of breast cancer diagnosed in patients taking and recently taking combined hormonal contraceptives relative to the total risk of developing breast cancer is small. These studies did not provide evidence of causality. The reasons for the observed increased risk may be due to earlier diagnosis of breast cancer in patients taking COCs, the biological effects of COCs, or a combination of both factors. Malignant neoplasms of the breast in patients who had ever taken COCs were, as a rule, less advanced clinically than in women who had never taken COCs.

In women who took COCs, benign and, even more rarely, malignant liver tumors were observed in rare cases. In some cases, such tumors led to life-threatening intra-abdominal bleeding.

In women taking COCs, if there is severe pain in the upper abdomen, an enlarged liver, or signs of intra-abdominal bleeding, a liver tumor should be suspected as part of the differential diagnosis.

Other conditions

In women with hypertriglyceridemia or a family history of hypertriglyceridemia, the possible increased risk of pancreatitis should be considered when taking combined hormonal contraceptives.

Although small increases in blood pressure have been reported in many women taking COCs, clinically significant increases are rare. No relationship was found between taking COCs and clinically manifested arterial hypertension. However, in the case of ongoing clinically significant arterial hypertension while taking COCs, it is advisable to stop taking COCs and begin treatment for arterial hypertension. If necessary, taking COCs can be resumed if normal blood pressure values ​​have been achieved with antihypertensive therapy.

The following conditions have been reported to develop or worsen during pregnancy and COC use (however, the association with COC use has not been conclusively proven):

• jaundice and/or itching associated with cholestasis;
• formation of gallstones;
• porphyria;
• systemic lupus erythematosus;
• hemolytic-uremic syndrome;
• Sydenham's chorea;
• herpes during pregnancy;
• hearing loss caused by otosclerosis, angioedema (including hereditary).

Acute or chronic liver dysfunction may require discontinuation of COCs until liver function tests return to normal. Recurrence of cholestatic jaundice, which first occurred during pregnancy or during previous use of sex steroid hormones, requires discontinuation of COC use.

Although COCs may affect peripheral insulin resistance and glucose tolerance, there is no evidence to support the need for changes in treatment regimen in diabetic patients taking combined hormonal contraceptives. However, women with diabetes who take combined hormonal contraceptives should be under close medical supervision.

An increased likelihood of developing ulcerative colitis and Crohn's disease has been associated with use of combined hormonal contraceptives.

Chloasma can sometimes develop (especially in women with a history of chloasma during pregnancy). Patients prone to chloasma should avoid exposure to sunlight or ultraviolet radiation while taking combined hormonal contraceptives.

When choosing your contraceptive method(s), you should take all of the information above into account.

Medical examination/consultation

Before starting or re-prescribing Regulon®, a thorough medical history (including family history) should be taken and pregnancy should be excluded. Blood pressure should be measured and a physical examination should be performed, guided by information on contraindications and special instructions and precautions. It is important to draw a woman’s attention to the risk of venous and arterial thrombosis, including the risk from the use of Regulon® in comparison with other CHCs, to the symptoms of VTE and ATE, as well as to established risk factors and actions taken in case of suspected development of thrombosis.

It is important that the woman read the patient information leaflet carefully and follow the recommendations contained therein. The frequency and type of examinations should be based on practical recommendations and adapted individually for each woman.

A woman should be warned that hormonal contraceptives do not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Decreased contraceptive effectiveness

The effectiveness of combined hormonal contraceptives may be reduced by missed pills, gastrointestinal disorders, or concomitant use of other medications.

Due to the risk of reducing the concentration of the drug in plasma, as well as reducing its clinical effects, simultaneous use with herbal preparations containing St. John's wort (Hypericum perforatum) should be avoided.

Menstrual cycle control

While taking any combined hormonal contraceptives, irregular bleeding may occur (“spotting” or “breakthrough” bleeding), especially during the first months of use. Therefore, assessing any irregular bleeding is only meaningful after an adaptation period of approximately three cycles.

If irregular bleeding recurs or develops after previous regular cycles, you should pay attention to non-hormonal causes of these conditions and exclude malignant neoplasms or pregnancy. A diagnostic curettage may be performed.

Some women experience bleeding "on the dosage regimen", it is unlikely that the woman will become pregnant. However, if before the first absence of withdrawal bleeding, combined hormonal contraceptives were not taken in accordance with the instructions, or there are no two withdrawal bleedings in a row, then pregnancy should be excluded before continuing to take combined hormonal contraceptives.

Increased ALT activity

During clinical trials in patients using drugs containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin for the treatment of hepatitis C viral infections, an increase in ALT activity was detected that was more than 5 times the ULN and occurred more often in women using ethinyl estradiol-containing drugs such as combined hormonal contraceptives.

Regulon® contains lactose, so the drug should not be taken by patients with rare hereditary diseases such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.

Impact on the ability to drive vehicles and operate machinery

There were no effects on the ability to drive vehicles and machinery.