Lindinet 20

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LINDYNETTE 20 (LINDYNETTE 20)

Composition:

Active substances: ethinylestradiol, gestodene;

One tablet contains 0.02 mg of ethinylestradiol and 0.075 mg of gestodene;

Excipients: sodium calcium edetate, magnesium stearate, colloidal anhydrous silicon dioxide, povidone, corn starch, lactose monohydrate, quinoline yellow (E 104), titanium dioxide (E 171), macrogol 6000, talc, calcium carbonate, sucrose.

Pharmaceutical form. Coated tablets.

Main physicochemical properties: light-yellow, round, biconvex coated tablets, without inscription on either side. Diameter – approximately 5.6 mm, nominal mass – 90.0 mg.

Pharmacotherapeutic group. Systemic hormonal contraceptives. Fixed combinations of progestogens and estrogens. ATC code G03A A10.

Pharmacological properties.

Pharmacodynamics.

Combined oral contraceptives act by suppressing gonadotropins. Although the primary mechanism of action is the inhibition of ovulation, other mechanisms—including changes in cervical mucus (which increases the difficulty of sperm penetration into the uterus) and the endometrium (which reduces the likelihood of implantation of a fertilized egg)—contribute to the contraceptive effect of the drug.

When taken correctly and continuously, the method failure rate of combined oral contraceptives is 0.1% per year. However, with typical use, the overall method failure rate of combined oral contraceptives is 5% per year. The effectiveness of most contraceptive methods depends on how reliably they are used. Method failure with combined oral contraceptives is most commonly due to missed tablets.

Pharmacokinetics.

Gestodene.

Absorption. Orally administered gestodene is rapidly and almost completely absorbed. Maximum serum concentration is reached within 1 hour after a single dose. The bioavailability of gestodene is approximately 99%.

Distribution. In serum, gestodene is primarily bound to sex hormone-binding globulin (SHBG) (50–70%) and to a lesser extent to serum albumin. Only 1–2% of the total serum concentration exists in the free steroid form.

The increase in SHBG levels induced by ethinylestradiol leads to an increase in the amount of gestodene bound to plasma proteins, resulting in an increased SHBG-bound fraction and a decreased albumin-bound fraction. With repeated dosing, gestodene accumulates in serum. Steady-state concentrations are reached in the second half of the cycle, when serum drug concentrations increase by 3–5 times.

Biotransformation. Gestodene is completely metabolized through reduction of the C3-keto group and the delta-4 double bond, as well as through multiple hydroxylation steps. It has not been established whether gestodene has a significant effect on the kinetics of ethinylestradiol when administered concomitantly.

Elimination. Serum levels of gestodene decline in two phases. With repeated administration, the terminal elimination half-life is approximately 20–28 hours. Metabolites are excreted in greater amounts in urine than in feces.

Ethinylestradiol.

Absorption. Orally administered ethinylestradiol is rapidly and almost completely absorbed. Maximum serum concentration is reached within 1–2 hours after administration. The bioavailability of ethinylestradiol, due to presystemic conjugation and first-pass metabolism in the liver, is approximately 40–60%.

Distribution. Ethinylestradiol is completely but non-specifically bound to albumin (about 98%) and causes an increase in the concentration of sex hormone-binding globulin (SHBG) in serum. Steady-state plasma concentrations are achieved in the second half of the cycle, when plasma drug concentrations increase by 25–50% compared to a single dose.

Biotransformation. Ethinylestradiol undergoes presystemic conjugation in the mucosa of the small intestine and in the liver, entering the enterohepatic circulation. The primary oxidative reaction is 2-hydroxylation catalyzed by cytochrome P450 enzymes. The compound forms a large number of different hydroxylated and ethylated metabolites, present as free metabolites as well as glucuronide and sulfate conjugates.

Elimination. Serum concentrations of ethinylestradiol decrease in two phases. The terminal elimination half-life of ethinylestradiol is 16–18 hours. Metabolites of ethinylestradiol, in the form of glucuronide and sulfate conjugates, are excreted in greater amounts in feces than in urine.

Clinical characteristics.

Indications.

Oral contraception.

When deciding to prescribe Lindinet 20, it is necessary to consider the individual woman's current risk factors, especially risk factors for venous thromboembolism (VTE), and the level of VTE risk associated with the use of Lindinet 20 compared to other combined hormonal contraceptives (see sections "Contraindications" and "Special precautions").

Contraindications.

Lindinet 20 is contraindicated in women with the presence or development of the following conditions:

• Hypersensitivity to the active substances or to any of the excipients.
• Presence or risk of venous thromboembolism (VTE):
  • venous thromboembolism – current VTE (anticoagulant therapy) or history of VTE (e.g., deep vein thrombosis [DVT] or pulmonary embolism [PE]);
  • known hereditary or acquired predisposition to venous thromboembolism, such as activated protein C resistance (APC, including factor V Leiden), antithrombin III deficiency, protein C deficiency, protein S deficiency;
  • major surgery with prolonged immobilization (see section "Special precautions");
  • increased risk of venous thromboembolism due to the presence of multiple risk factors (see section "Special precautions").
• Presence or risk of arterial thromboembolism (ATE):
  • arterial thromboembolism – current arterial thromboembolism, history of arterial thromboembolism (e.g., myocardial infarction) or prodromal state (e.g., angina pectoris);
  • cerebrovascular disease – current stroke, history of stroke, or prodromal state (e.g., transient ischemic attack, TIA);
  • known hereditary or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinemia and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
  • history of migraine with focal neurological symptoms;
  • increased risk of arterial thromboembolism due to the presence of multiple risk factors (see section "Special precautions") or due to the presence of one of the serious risk factors such as:
  • diabetes mellitus with vascular complications;
  • severe arterial hypertension;
  • severe dyslipoproteinemia.
• Presence of pancreatitis or history of pancreatitis if it was associated with severe hypertriglyceridemia.
• Presence of severe hepatic dysfunction or such conditions in medical history (until liver function has recovered).
• Presence of liver tumors (benign or malignant) or such tumors in medical history.
• Known or suspected steroid-dependent malignant tumors (e.g., genital organs).
• Current or past history of hormone-dependent breast cancer (see section "Special precautions").
• Undiagnosed abnormal vaginal bleeding.

Concomitant use of Lindinet 20 with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, medicinal products containing glecaprevir/pibrentasvir, or sofosbuvir/velpatasvir/voxilaprevir is contraindicated (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Note. Refer to the appropriate prescribing information for other medicinal products used concomitantly to identify potential interactions.

Pharmacodynamic interactions

During clinical studies involving patients receiving medications for the treatment of hepatitis C virus (HCV) infection containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, increased levels of transaminases (ALT) more than 5 times above the upper limit of normal (ULN) were observed. This occurred significantly more frequently in women receiving medications containing ethinylestradiol, including combined hormonal contraceptives (CHCs). Additionally, ALT elevation was also observed during treatment with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir in women taking medications containing ethinylestradiol, such as CHCs (see section "Contraindications"). Therefore, patients taking Lindinet 20 should switch to an alternative method of contraception (e.g., progestogen-only contraceptives or non-hormonal methods) prior to initiating therapy with the aforementioned combination medicinal products. Use of Lindinet 20 may be resumed 2 weeks after completion of treatment with these combination medicinal products.

Pharmacokinetic interactions

Effect of other medicinal products on Lindinet 20

Interactions are possible with drugs that induce microsomal enzymes, which may lead to increased clearance of sex hormones and result in breakthrough bleeding and/or loss of contraceptive efficacy.

Treatment

Enzyme induction may be observed within a few days of starting treatment. Maximum enzyme induction is usually observed within a few weeks. After discontinuation of treatment, enzyme induction may persist for approximately 4 weeks.

Short-term treatment

Women receiving treatment with enzyme-inducing agents should use a barrier method or another contraceptive method in addition to the use of COCs. The barrier method should be used throughout the entire period of concomitant medication treatment and for 28 days after discontinuation of such treatment.

If therapy with an enzyme-inducing agent continues beyond the end of the COC pack, the next COC pack should be started immediately after finishing the previous one, without the usual break in tablet intake.

Long-term treatment

Women receiving long-term treatment with agents that are enzyme inducers are advised to use another reliable non-hormonal method of contraception.

Cases of such interactions have been reported in the literature.

Substances increasing COC clearance (reduced COC efficacy due to enzyme induction)

Barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin, and HIV medications – ritonavir, nevirapine, and efavirenz; possible interaction also with felbamate, griseofulvin, oxcarbazepine, topiramate, and products containing St. John's wort (Hypericum perforatum).

Substances with variable effect on COC clearance

When used concomitantly with COCs, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with hepatitis C virus inhibitors, may increase or decrease plasma concentrations of estrogens or progestins. The net effect of this interaction may be clinically significant in some cases.

Therefore, when using medications for the treatment of HIV/hepatitis C virus concomitantly, refer to the prescribing information for these medications to identify potential interactions and obtain appropriate recommendations. In case of doubt, women receiving therapy with protease inhibitors or non-nucleoside reverse transcriptase inhibitors are advised to use an additional barrier method of contraception.

Effect of Lindinet 20 on other medicinal products

Oral contraceptives may affect the metabolism of certain other active substances. Consequently, plasma and tissue concentrations of such substances may increase (e.g., cyclosporine, theophylline) or decrease (e.g., lamotrigine, tizanidine, levothyroxine).

Special precautions for use.

Warning

If a woman has any of the conditions or risk factors listed below, the appropriateness of using Linidinet 20 should be discussed with the patient.

If any of the symptoms or risk factors listed below worsen or develop, women are advised to consult their physician, who will decide whether treatment with Linidinet 20 should be discontinued.

Disorders of blood circulation.

Risk of venous thromboembolism (VTE)

The use of any combined oral contraceptive (COC) increases the risk of venous thromboembolism (VTE) compared to non-use.

COCs containing levonorgestrel, norgestimate, or norethisterone are associated with a lower risk of VTE. Other COCs, such as Linidinet 20, may be associated with a twofold higher risk. The decision to prescribe any COC other than one with a lower VTE risk should only be made after discussing with the patient to ensure she understands the VTE risk associated with Linidinet 20, appreciates how existing risk factors affect the likelihood of VTE, and is aware that the risk of VTE is highest during the first year of COC use. There is also some evidence that this risk increases when restarting a COC after a break of 4 weeks or more.

Approximately 2 out of 10,000 women who do not use COCs and are not pregnant will develop VTE within one year. However, in any individual woman, the risk may be substantially higher depending on existing risk factors (see information below).

It is estimated that [1] 9–12 out of 10,000 women who use COCs containing gestodene will develop VTE within one year; this can be compared with approximately 6 cases [2] among women using COCs containing levonorgestrel.

In both cases, the annual rate of VTE is lower than the rate expected during pregnancy or the postpartum period.

VTE may be fatal in 1–2% of cases.

Very rare cases of thrombosis in other vessels, such as arteries and veins of the liver, kidneys, mesenteric vessels, or retinal vessels, have been reported in women using COCs.

Number of VTE cases per 10,000 women per year

Risk factors for VTE

The risk of venous thromboembolic complications in women using COCs may be substantially increased in patients with additional risk factors, particularly multiple risk factors (see Table 1).

Linidinet 20 is contraindicated if the patient has multiple risk factors leading to a high risk of venous thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the increase in risk may be greater than the sum of the individual factors—in such a case, the overall VTE risk for the patient should be considered. If the benefit-risk balance is considered unfavorable, COCs should not be prescribed (see section "Contraindications").

Table 1

Risk factors for VTE

There is no consensus regarding the possible influence of varicose veins and superficial thrombophlebitis on the onset or progression of venous thrombosis.

The risk of thromboembolism should be considered during pregnancy, particularly during the 6-week period following childbirth (information on use during pregnancy or breastfeeding is provided in the section "Use during pregnancy or breastfeeding").

Symptoms of VTE (deep vein thrombosis and pulmonary embolism)

If any symptoms occur, women are advised to seek immediate medical attention and inform their physician that they are taking a COC.

Symptoms of deep vein thrombosis (DVT) may include:

• unilateral swelling of the leg and/or foot or of a segment along the vein in the leg;
• pain or tenderness in the leg, which may only be felt while standing or walking;
• a sensation of warmth in the affected leg; redness or discoloration of the skin on the leg.

Symptoms of pulmonary embolism (PE) may include:

• sudden unexplained shortness of breath or rapid breathing;
• sudden cough, possibly with hemoptysis;
• acute chest pain;
• severe dizziness;
• rapid or irregular heartbeat.

Some of these symptoms (e.g., shortness of breath, cough) are nonspecific and may be misinterpreted as more common or less serious conditions (e.g., respiratory tract infections).

Other signs of vascular occlusion may include: sudden pain, swelling, and bluish discoloration of a limb.

Symptoms of ocular vessel occlusion may vary from painless blurred vision, which may progress to vision loss. Sometimes, vision loss may occur almost instantaneously.

Risk of arterial thromboembolism (ATE)

Epidemiological studies have associated the use of COCs with an increased risk of arterial thromboembolism (myocardial infarction) or cerebrovascular events (e.g., transient ischemic attack, stroke). Arterial thromboembolic complications can be fatal.

Risk factors for ATE

The risk of arterial thromboembolic complications or cerebrovascular events among women taking COCs increases in those who have risk factors (see Table 2). Lindinet 20 is contraindicated if the patient has one serious risk factor or multiple risk factors leading to a high risk of arterial thromboembolism (see section "Contraindications"). If a woman has more than one risk factor, the increase in risk may be greater than the sum of the individual factors—in such cases, the overall ATE risk for the patient should be carefully evaluated. If the benefit-risk balance is considered unfavorable, COCs should not be prescribed (see section "Contraindications").

Table 2

Risk factors for ATE

ATE Symptoms

If symptoms occur, women are advised to seek immediate medical attention and inform their doctor that they are taking COCs.

Symptoms of cerebrovascular disorders may include:

• sudden numbness or weakness of the face, arm, or leg, especially on one side of the body;
• sudden difficulty walking, dizziness, loss of balance or coordination;
• sudden confusion, trouble speaking or understanding speech;
• sudden vision changes in one or both eyes;
• sudden, severe, or prolonged headache with no known cause;
• loss of consciousness or fainting with or without seizures.

Transient symptoms may indicate a transient ischemic attack (TIA).

Symptoms of myocardial infarction (MI) may include:

• chest pain, discomfort, pressure, heaviness, or tightness in the chest or below the sternum;
• discomfort radiating to the back, jaw, throat, arm, or stomach;
• feeling of fullness, indigestion, or shortness of breath;
• excessive sweating, nausea, vomiting, or dizziness;
• unusual weakness, anxiety, or breathlessness;
• rapid or irregular heartbeat.

Oncological diseases.

The most important risk factor for cervical cancer is persistent papillomavirus infection (human papillomavirus, HPV). Results of some epidemiological studies suggest that long-term use of COCs may be associated with an increased risk of cervical cancer in women infected with HPV. However, this assertion remains controversial, as it is unclear to what extent these studies account for confounding risk factors (e.g., cervical screening practices or sexual behavior, including use of barrier contraception methods).

Lindinet 20 is contraindicated in women with current or past history of hormone-dependent breast cancer (see section "Contraindications").

Epidemiological studies have not shown a consistent association between the use of combined oral contraceptives (COCs) and the risk of developing breast cancer. Studies do not show a link between current or past use of COCs and the risk of breast cancer. However, some studies have reported a slight increase in the risk of breast cancer among women who are currently using or have recently used COCs (<6 months since last use) and those who have used COCs for a prolonged period (see section "Adverse Reactions").

In rare cases, benign and even more rarely malignant liver tumors have been observed in women taking COCs, which in some instances led to life-threatening intra-abdominal hemorrhage. In cases of severe epigastric pain, hepatomegaly, or signs of intra-abdominal bleeding, the possibility of a liver tumor should be considered in differential diagnosis when using oral contraceptives.

Other conditions.

Depressed mood and depression are common adverse reactions during hormonal contraceptive use (see section "Adverse Reactions"). Depression can be severe and is a known risk factor for suicidal behavior and suicide. Women should be informed of the need to consult a physician if mood swings or symptoms of depression occur, even shortly after starting treatment.

Women with a history of depression who are taking COCs require careful monitoring, and the drug should be discontinued if depression recurs. Patients who develop severe depression while taking COCs should discontinue the drug and an alternative contraceptive method should be prescribed to assess whether symptoms are related to the medication.

Women with hypertriglyceridemia or a family history of this condition are at increased risk of developing acute pancreatitis when using combined oral contraceptives.

Although a slight increase in blood pressure has been reported in many women taking COCs, clinically significant hypertension is rare. However, if persistent clinically evident arterial hypertension develops during COC use, it is advisable to discontinue COCs and treat the hypertension. If appropriate, COC use may be resumed after normal blood pressure is achieved with antihypertensive therapy.

The following conditions/states have been reported to occur or worsen during pregnancy and during COC use, but their causal relationship to COC use has not been definitively established: cholestasis-related jaundice and/or pruritus, gallstone formation, porphyria, systemic lupus erythematosus, hemolytic-uremic syndrome, Sydenham’s chorea, herpes gestationis, hearing loss associated with otosclerosis.

Exogenous estrogens may induce or exacerbate symptoms of hereditary or acquired angioedema.

Acute or chronic liver dysfunction may necessitate discontinuation of COCs until liver function tests return to normal. Liver disease may significantly reduce the metabolism of steroid hormones. COC use should be discontinued in case of recurrence of cholestatic jaundice and/or pruritus that first occurred during pregnancy or previous use of sex hormones.

Although COCs may affect peripheral insulin resistance and glucose tolerance, there are no data indicating a need to alter therapy in diabetic women taking low-dose COCs (containing <0.05 mg ethinylestradiol). However, women with diabetes should be carefully monitored during COC use.

Cases of Crohn’s disease and ulcerative colitis have been reported in women using COCs.

Melasma may occasionally occur, particularly in women with a history of melasma during pregnancy. Women prone to melasma should avoid direct sunlight or ultraviolet radiation during COC use.

Conditions requiring special attention.

Medical examination/consultation.

Before initiating Lindinet 20, a detailed family history should be obtained and a general medical and gynecological examination should be performed, taking into account contraindications (see section "Contraindications") and special precautions (see section "Special Precautions"). Pregnancy must be ruled out. This examination should be repeated periodically. The medical examination should include blood pressure measurement, breast examination, abdominal palpation, gynecological examination with cytological testing, and laboratory tests.

It is important to inform women about venous and arterial thrombosis, including the risk associated with Lindinet 20 compared to other COCs, symptoms of VTE and ATE, known risk factors, and actions to take in case of suspected thrombosis.

Women should be advised to carefully read the package leaflet and follow the instructions provided. The frequency and nature of examinations should be based on established clinical guidelines and adapted to the individual woman.

Women should be informed that the medication does not protect against sexually transmitted infections, including HIV (AIDS).

Other information.

Reduced efficacy

The efficacy of combined oral contraceptives may be reduced in case of missed tablet intake (see section "Dosage and Administration"), gastrointestinal disturbances (see section "Dosage and Administration"), or concomitant use of other medicinal products (see section "Interaction with other medicinal products and other forms of interaction").

Controlled cycle bleeding

Breakthrough bleeding (spotting or intermenstrual bleeding) may occur when taking any oral contraceptives, especially during the first few months. Therefore, evaluation of irregular intermenstrual bleeding should only be performed after an adaptation period of three cycles.

If irregular bleeding persists after the adaptation period or occurs after a period of regular cycles, non-hormonal causes of bleeding should be considered and appropriate diagnostic measures taken to exclude malignancy and pregnancy. Diagnostic procedures may include curettage.

In some women, menstruation may not occur during the tablet-free interval.

If COCs are taken according to instructions in the section "Dosage and Administration," pregnancy is unlikely. However, if the drug has been taken irregularly or if menstruation is absent for two consecutive cycles, pregnancy must be ruled out before continuing COC use.

Pediatric population

Lindinet 20 is recommended for use only after the first menstrual period.

Elderly patients

Use of combined oral contraceptives after menopause is not indicated.

Liver function impairment

Lindinet 20 is contraindicated in women with impaired liver function (see section "Contraindications").

Renal function impairment

Data on use of the drug in patients with renal impairment are lacking.

Effect on results of laboratory and other diagnostic tests

Use of combined oral contraceptives may cause certain physiological changes that may affect results of some laboratory tests, including:

• liver function parameters (including decreased bilirubin and alkaline phosphatase levels), thyroid function (increased total T3 and T4 due to elevated thyroxine-binding globulin (TBG), decreased free T3 uptake), adrenal function (increased plasma cortisol, increased cortisol-binding globulin, decreased dehydroepiandrosterone sulfate (DHEA-S)), and kidney function (increased plasma creatinine and decreased creatinine clearance);
• levels of plasma carrier proteins such as corticosteroid-binding globulin and lipid/lipoprotein fractions;
• carbohydrate metabolism parameters;
• coagulation and fibrinolysis parameters;
• decreased plasma folate levels.

Changes usually remain within the normal laboratory reference range.

Excipients

This medicinal product contains lactose and sucrose.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Patients with rare hereditary problems of fructose intolerance, sucrase-isomaltase deficiency, or glucose-galactose malabsorption should not take this medicine.

This medicinal product contains less than 1 mmol (23 mg)/tablet of sodium, i.e., essentially "sodium-free."

Use during pregnancy or breastfeeding.

Pregnancy.

Pregnancy should be excluded before starting Lindinet 20.

If pregnancy occurs during use of an oral contraceptive, treatment should be stopped immediately.

There are no convincing data that estrogens and progestins contained in combined oral contraceptives cause congenital malformations in children if pregnancy occurs accidentally during COC use.

When re-prescribing Lindinet 20, the increased risk of VTE in the postpartum period should be considered (see sections "Dosage and Administration" and "Special Precautions").

Breastfeeding. Small amounts of steroids contained in oral hormonal contraceptives and/or their metabolites have been reported to be excreted in breast milk, along with some adverse reactions in infants, including jaundice and breast enlargement. Oral contraceptives may affect lactation, as their use may reduce the quantity and alter the composition of breast milk.

Use of combined oral contraceptives is generally not recommended until complete cessation of breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Lindinet 20 has no effect or negligible effect on the ability to drive or operate machinery.

Method of Administration and Dosage

For oral use only.

Tablets should be taken daily at approximately the same time, in the order indicated on the blister pack. One tablet should be taken daily (preferably at the same time each day) for 21 consecutive days. After this, a 7-day break from taking tablets should be observed. During this 7-day break, a withdrawal bleed resembling menstruation is expected to occur. This bleeding usually begins on the 2nd or 3rd day after taking the last tablet and may continue until the start of the next pack.

The next day after the 7-day break, tablet intake should resume with a new pack containing 21 tablets.

First Use of the Medicinal Product

The first tablet of Lindinet 20 should be taken on the first day of the menstrual cycle.

Tablet intake may also begin on days 2 to 7 of menstruation; however, in this case, additional non-hormonal contraceptive methods (e.g., condoms, spermicides) must be used for the first 7 days of tablet intake.

Switching to Lindinet 20 from another combined contraceptive (combined oral contraceptives /COCs/, vaginal ring, or transdermal patch)

The first tablet of Lindinet 20 should be taken the day after the last active tablet from the previous combined oral contraceptive pack, but no later than the day after the usual tablet-free (or placebo tablet) interval of the previous oral contraceptive pack.

When switching from a vaginal ring or transdermal patch to Lindinet 20, it is recommended to start taking Lindinet 20 on the day of removal of the vaginal ring or transdermal patch, but no later than the day a new ring or patch would normally be applied.

Switching to Lindinet 20 from a progestogen-only contraceptive (the "mini-pill", injections, implant, or intrauterine system)

Progestogen-only tablets may be discontinued at any time, and Lindinet 20 should be started the following day. Switching from an implant can occur on the day of implant removal or intrauterine system removal. When switching from injectable contraceptives, tablet intake should begin on the day the next injection would have been administered. In all these cases, additional contraceptive methods must be used for the first 7 days.

Use of Lindinet 20 after a first-trimester abortion

Tablet intake may begin immediately after a first-trimester abortion; in this case, there is no need to use additional contraceptive methods.

Use of Lindinet 20 after childbirth or second-trimester abortion

Information regarding use during breastfeeding is described in the section "Use during pregnancy or breastfeeding".

Since the postpartum period is associated with an increased risk of thromboembolism, Lindinet 20 should not be started earlier than 28 days after childbirth in women who are not breastfeeding, or after a second-trimester abortion. Women should be advised to use an additional backup non-hormonal contraceptive method for the first 7 days of tablet intake. However, if sexual intercourse has already occurred after childbirth or abortion, pregnancy must be excluded before starting Lindinet 20, or the woman should wait for the onset of the first menstruation (see also sections "Special Warnings and Precautions for Use" and "Use during pregnancy or breastfeeding").

Missed tablet intake

If a tablet is taken less than 12 hours late, contraceptive protection is not reduced. The missed tablet should be taken as soon as remembered. The next tablet should be taken at the usual time. If the delay in taking the tablet exceeds 12 hours, contraceptive protection may be reduced. In such cases, two main rules should be followed:

1. The tablet-free interval must never exceed 7 days.
2. Adequate suppression of the hypothalamic-pituitary-ovarian system is achieved only after 7 consecutive days of tablet intake.

Accordingly, the following practical recommendations should be followed:

Week 1

The missed tablet should be taken as soon as possible, even if this means taking two tablets at the same time. After this, continue taking tablets at the usual time. Additionally, a barrier method of contraception (e.g., condom) should be used for the next 7 days. If sexual intercourse occurred in the previous 7 days, the possibility of pregnancy should be considered. The more tablets missed and the closer the missed dose is to the 7-day tablet-free interval, the higher the risk of pregnancy.

Week 2

The missed tablet should be taken as soon as possible, even if two tablets have to be taken at the same time. After this, continue taking tablets at the usual time. If tablets were taken correctly in the 7 days before the missed dose, additional contraceptive methods are not required. Otherwise, or if more than one tablet is missed, a barrier method of contraception should be used for the next 7 days.

Week 3

The risk of reduced contraceptive effect increases as the 7-day tablet-free interval approaches. However, by adjusting the dosing schedule, a reduction in contraceptive protection can be avoided. If one of the following options is followed, additional contraceptive methods are not required, provided tablets were taken correctly in the 7 days before the missed dose. If this is not the case, the first of the following options should be followed, and additional contraceptive methods should be used for the next 7 days.

1. The missed tablet should be taken as soon as possible, even if two tablets have to be taken at the same time. After this, continue taking tablets at the usual time. The next pack should be started immediately after finishing the current pack, i.e., no tablet-free interval should occur. It is unlikely that a withdrawal bleed will occur before finishing the second pack, although spotting or breakthrough bleeding may occur.
2. Alternatively, tablet intake from the current pack may be discontinued. In this case, the tablet-free interval should be 7 days, including the days of missed tablets, after which tablet intake from the next pack should be started. If a woman wishes to start the next pack on her usual starting day, the 7-day tablet-free interval should be shortened accordingly.

If no withdrawal bleed occurs during the first usual tablet-free interval after missed tablets, pregnancy should be considered.

Actions in case of vomiting and/or diarrhea

If vomiting or diarrhea occurs within 4 hours after taking the tablet, the active ingredient may not have been completely absorbed. In such cases, the recommendations for "Missed tablet intake" should be followed. If the patient does not wish to deviate from the usual schedule, the missed tablets should be taken from a spare pack.

Delaying or accelerating the menstrual cycle

To delay menstruation, continue taking tablets from a new pack without a 7-day tablet-free interval. Menstrual bleeding can be delayed as long as necessary, until the end of the second pack. During the delay, spotting or breakthrough bleeding may occur. Regular intake of Lindinet 20 can be resumed after a standard 7-day tablet-free interval.

To accelerate the onset of menstrual bleeding, the 7-day tablet-free interval can be shortened by the desired number of days.

The shorter the tablet-free interval, the higher the risk that menstruation will not occur or that spotting or breakthrough bleeding will occur during intake of tablets from the next pack.

Children

Lindinet 20 is indicated for use only after the onset of regular menstruation.

Overdose

Symptoms of oral contraceptive overdose in adults and children may include: nausea, vomiting, breast tenderness, dizziness, abdominal pain, somnolence/fatigue; in young girls, light vaginal bleeding may occur. There is no specific antidote; treatment is symptomatic.

Adverse reactions.

The use of oral contraceptives is associated with an increased risk of the adverse reactions listed below:

• Arterial and venous thrombotic and thromboembolic complications* (frequency: rare) (see also section "Special precautions for use");
• Cervical intraepithelial neoplasia and cervical cancer;
• Breast cancer;
• Benign liver tumors (focal nodular hyperplasia, hepatic adenoma).

*The use of COCs is associated with an increased risk of arterial and venous thrombotic and thromboembolic complications, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis, and pulmonary embolism. Detailed information on these adverse reactions is provided in the section "Special precautions for use".

The adverse effects listed below are classified according to the following frequency categories: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from available data).

Infections and infestations

Common: vaginitis, including candidiasis.

Benign, malignant and unspecified neoplasms (including cysts and polyps)

Very rare: hepatocellular carcinoma.

Immune system disorders

Rare: anaphylactic/anaphylactoid reactions, including rare cases of urticaria, angioedema, and severe reactions with symptoms involving the respiratory and circulatory systems.

Very rare: exacerbation of systemic lupus erythematosus.

Frequency not known: exacerbation of symptoms of hereditary and acquired angioedema.

Metabolism and nutrition disorders

Uncommon: changes in lipid levels, including hypertriglyceridemia; changes in appetite (increased or decreased).

Rare: decreased plasma folate levels*, glucose intolerance.

Very rare: exacerbation of porphyria.

Psychiatric disorders

Common: mood changes, including depression, changes in libido.

Nervous system disorders

Very common: headache, including migraine.

Common: nervousness, dizziness.

Very rare: exacerbation of chorea.

Eye disorders

Rare: intolerance to contact lenses.

Very rare: optic neuritis**; retinal vascular thrombosis.

Cardiac disorders

Uncommon: arterial hypertension.

Vascular disorders

Rare: venous thromboembolism (VTE), arterial thromboembolism (ATE).

Very rare: exacerbation of varicose veins.

Gastrointestinal disorders

Common: nausea, vomiting, abdominal pain.

Uncommon: abdominal cramps; bloating.

Very rare: pancreatitis, ischemic colitis.

Frequency not known: inflammatory bowel diseases (Crohn’s disease, ulcerative colitis).

Hepatobiliary disorders

Rare: cholestatic jaundice.

Very rare: gallbladder disease, including gallstones***.

Frequency not known: hepatocellular disorders (e.g., hepatitis, liver function abnormalities).

Skin and subcutaneous tissue disorders

Common: acne.

Uncommon: rash, chloasma (melasma), which may be persistent; hirsutism, alopecia.

Rare: erythema nodosum.

Very rare: erythema multiforme.

Renal and urinary disorders

Very rare: hemolytic-uremic syndrome.

Reproductive system and breast disorders

Very common: breakthrough bleeding/spotting.

Common: breast tenderness, increased sensitivity, breast enlargement, breast discharge; dysmenorrhea; changes in menstrual pattern; changes in cervical secretion and erosive changes; amenorrhea.

General disorders and administration site conditions

Common: fluid retention/edema.

Investigations

Common: weight change (increase or decrease).

Uncommon: increased blood pressure, changes in plasma lipid levels, including hypertriglyceridemia.

Rare: decreased plasma folate levels*.

*Lipid levels in plasma may decrease under the influence of combined oral contraceptives. This may be clinically significant if a woman becomes pregnant shortly after discontinuation of combined oral contraceptives.

**Optic neuritis may lead to complete or partial loss of vision.

***The use of combined oral contraceptives may worsen existing gallbladder disease and accelerate the development of this condition in women who previously had no symptoms.

In women with hereditary angioedema, exogenous estrogens may trigger or exacerbate angioedema symptoms.

In five studies comparing the risk of developing breast cancer in women who had ever used COCs (currently or in the past) and those who had never used COCs, no association was found between COC use (ever) and the risk of developing breast cancer, with effect estimates ranging from 0.90 to 1.12.

In three studies comparing the risk of developing breast cancer in women who currently or recently used COCs (<6 months since last use) and those who had never used COCs, one study found no association between breast cancer risk and COC use. The other two studies found a 1.19–1.33 increased relative risk in women who currently or recently used COCs. Both studies found an increased risk of breast cancer in women who used COCs for a long duration, with relative risk ranging from 1.03 for less than one year of COC use to approximately 1.4 for more than 8–10 years of COC use.

Interactions

Interactions of other medicinal products (enzyme inducers) with oral contraceptives may lead to breakthrough bleeding and/or loss of contraceptive efficacy (see section "Interaction with other medicinal products and other forms of interaction").

Reporting suspected adverse reactions

Collecting information on suspected adverse reactions after drug registration is of great importance. This allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25°C in the original packaging to protect from light and moisture.

Keep out of reach of children.

Packaging. 21 film-coated tablets in a blister; 1 or 3 blisters together with a cardboard blister holder in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Gedeon Richter Plc.

Manufacturer's address and location of operations.

19-21, Demrédi Street, H-1103 Budapest, Hungary.

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[1] These estimates were derived from a pooled analysis of epidemiological studies using relative risks for different preparations compared to COCs containing levonorgestrel.

[2] Midpoint of the range 5–7 per 10,000 patient-years, based on relative risk for COCs containing levonorgestrel compared to approximately 2.3–3.6 in women not using COCs.