Lindinet 30

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LINDYNETTE 30 (LINDYNETTE 30)

Composition:

Active substances: ethinylestradiol, gestodene;

1 tablet contains 0.03 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. Film-coated tablets.

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

Pharmacotherapeutic group. Systemic hormonal contraceptives. Progestogens and estrogens, fixed combinations. 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 increase the difficulty of sperm penetration into the uterus) and the endometrium (which reduce the likelihood of implantation of a fertilized egg)—contribute to the contraceptive effect of the drug.

When used 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 of 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 as free steroid.

The increase in SHBG levels induced by ethinylestradiol leads to increased plasma protein binding of gestodene, resulting in an increase in the SHBG-bound fraction and a decrease in the albumin-bound fraction. With repeated dosing, gestodene accumulates in serum. Steady-state concentration is reached in the second half of the cycle, when serum concentrations of the drug increase 3–5 fold.

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. The terminal elimination half-life is approximately 16–18 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 concentration is achieved in the second half of the cycle, when plasma concentrations of the drug 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 and enters the enterohepatic circulation. The primary oxidative reaction is 2-hydroxylation by cytochrome P450 enzymes. The substance forms a large number of various hydroxylated and ethylated metabolites, present as free metabolites as well as conjugates with glucuronides and sulfate.

Elimination. Serum concentrations of ethinylestradiol decline 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 30, it is necessary to consider the current risk factors for the individual woman, particularly the risk factors for venous thromboembolism (VTE), and the extent to which the risk of VTE with Lindinet 30 is higher compared to other combined hormonal contraceptives (see sections "Contraindications" and "Special precautions").

Contraindications.

Lindinet 30 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, e.g., activated protein C resistance (APC, including factor V Leiden), antithrombin-III deficiency, protein C deficiency, protein S deficiency;
  • major surgical intervention with prolonged immobilization (see section "Special precautions");
  • increased risk of developing 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, e.g., hyperhomocysteinemia and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
  • history of migraine with focal neurological symptoms;
  • increased risk of developing 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 is associated with severe hypertriglyceridemia.
• Presence of severe hepatic dysfunction or such disorders in the past (until liver function has recovered).
• Presence of liver tumors (benign or malignant) or such tumors in the past.
• Known or suspected steroid-dependent malignant neoplasms (e.g., genital organs).
• Breast cancer that may be hormone-dependent, currently or in the past (see section "Special precautions").
• Undiagnosed abnormal vaginal bleeding.

Concomitant use of Lindinet 30 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 instructions for medical use of other medicinal products being used concomitantly to identify potential interactions.

Pharmacodynamic interactions

During clinical trials involving patients receiving medicinal products for the treatment of hepatitis C virus (HCV) infection containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, elevated levels of transaminases (ALT) more than 5 times above the upper limit of normal (ULN) were observed. This occurred significantly more frequently in women who were using medicinal products containing ethinylestradiol, including combined hormonal contraceptives (CHCs). Additionally, when treating with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, increased ALT levels were also observed in women taking medicinal products containing ethinylestradiol, such as CHCs (see section "Contraindications"). Therefore, women taking Lindinet 30 should switch to an alternative method of contraception (e.g., progestogen-only contraceptives or non-hormonal methods) prior to initiating therapy with the aforementioned combined medicinal products. Use of Lindinet 30 may be resumed 2 weeks after completion of treatment with these combined medicinal products.

Pharmacokinetic interactions

Effect of other medicinal products on Lindinet 30

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 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 inducers should temporarily use a barrier method or another contraceptive method in addition to using CHCs. The barrier method should be used throughout the entire period of concomitant medicinal product treatment and for 28 days after discontinuation of such treatment.

If treatment with an enzyme-inducing agent continues beyond the end of the pack of CHCs, the next pack of CHCs should be started immediately after finishing the previous one, without the usual tablet-free interval.

Long-term treatment

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

Cases of interaction have been reported in the literature.

Substances that increase CHC clearance (reduced CHC efficacy due to enzyme induction)

Barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin, and HIV treatments – 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 CHC clearance

When used concomitantly with CHCs, 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 medicinal products for the treatment of HIV/hepatitis C virus concomitantly, refer to the instructions for medical use of such products 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 30 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 the drug Lindinet 30 should be discussed with the patient.

If there is worsening of any condition or the appearance of any of the symptoms or risk factors listed below, women are advised to consult their physician, who will decide whether to discontinue the use of Lindinet 30.

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.

Preparations containing levonorgestrel, norgestimate, or norethisterone are associated with a lower risk of VTE. Other preparations, such as Lindinet 30, may be associated with twice the risk. The decision to use any preparation instead of a medicinal product with a lower risk of VTE should only be made after discussion with the patient to ensure that she understands the VTE risk associated with Lindinet 30, 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 use. There is also some evidence that this risk increases when restarting COCs 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 considerably higher depending on existing risk factors (see information below).

It is estimated that [1] 9–12 out of 10,000 women using 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 can result in fatal outcomes in 1–2% of cases.

Very rare cases of thrombosis in other blood 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 substantially increase in patients with additional risk factors, particularly multiple factors (see Table 1).

Lindinet 30 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 individual factors—in such a case, the overall VTE risk for the patient should be carefully considered. If the benefit-risk ratio 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 of these symptoms occur, women are advised to seek immediate medical attention and inform their physician that they are taking COCs.

Symptoms of deep vein thrombosis (DVT) may include:

• Unilateral swelling of the leg and/or foot or a segment along a 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 non-specific 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 development of a bluish discoloration of a limb.

Symptoms of ocular vessel occlusion may range from painless blurred vision, which may progress to vision loss. In some cases, vision loss may occur almost instantaneously.

Risk of arterial thromboembolism (ATE)

Epidemiological studies associate 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 30 is contraindicated if the patient has one serious risk factor or multiple risk factors for ATE that lead 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 help and inform the 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, speech or vision disturbances;
• sudden partial or complete vision loss in one or both eyes;
• sudden, severe, or prolonged headache of unknown origin;
• loss of consciousness 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, arm, or below the sternum;
• discomfort radiating to the back, jaw, throat, arm, or stomach;
• sensation of fullness, indigestion, or suffocation;
• excessive sweating, nausea, vomiting, or dizziness;
• unusual weakness, anxiety, or shortness of breath;
• rapid or irregular heartbeat.

Oncological diseases

The most important risk factor for cervical cancer is persistent human papillomavirus (HPV) infection. 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 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).

Lindinet 30 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 demonstrate a link between current or past use of COCs and the risk of breast cancer. However, some studies have reported a slight increase in breast cancer risk among women currently using or who recently used COCs (within <6 months of last use) and among 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 cases led to life-threatening intra-abdominal hemorrhage. In cases of severe epigastric pain, hepatomegaly, or signs of intra-abdominal bleeding, the possibility of liver tumor should be considered in differential diagnosis among women using oral contraceptives.

Other conditions

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

Women with a history of depression who are taking COCs require careful monitoring, and the drug should be discontinued in case of depression recurrence. Patients who develop severe depression during COC use should discontinue the drug and an alternative contraceptive method should be considered to assess the potential link with drug use.

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 hypertension develops during COC use, it is advisable to discontinue COCs and treat the hypertension. If appropriate, COC use may be resumed after achieving normal blood pressure with antihypertensive therapy.

The following conditions have been reported to occur or worsen during pregnancy and COC use, but their causal relationship with COC use has not been definitively established: jaundice and/or pruritus related to cholestasis, 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. Impaired liver function 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 the need to alter therapeutic regimens 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.

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

Conditions requiring special attention

Medical examination/consultation

Before initiating Lindinet 30, 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 excluded. 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 30 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 patient information 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 drug does not protect against sexually transmitted infections, including HIV (AIDS).

Other information

Reduced effectiveness

The effectiveness of combined oral contraceptives may be reduced in case of missed tablet intake (see section "Dosage and Administration"), gastrointestinal disorders (see section "Dosage and Administration"), or concomitant use of other medicinal products (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Control of shortened cycle

Intermenstrual bleeding (spotting or breakthrough bleeding) may occur during use of 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 appears after a period of regular cycles, non-hormonal causes of bleeding should be considered, and appropriate diagnostic measures should be taken to exclude tumors 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 the instructions in the section "Dosage and Administration," pregnancy is unlikely. However, if intake has been irregular or if menstruation is absent for two consecutive cycles, pregnancy must be excluded before continuing COC use.

Pediatric population

Lindinet 30 is recommended for use only after the first menstruation.

Elderly patients

The use of combined oral contraceptives after menopause is not indicated.

Liver function impairment

Lindinet 30 is contraindicated in women with impaired liver function (see section "Contraindications").

Renal function impairment

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

Effect on results of laboratory and other diagnostic tests

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

• liver function biochemical parameters (including decreased bilirubin and alkaline phosphatase levels), thyroid function (increased total T3 and T4 due to increased thyroxine-binding globulin (TBG), decreased free T3 uptake), adrenal function (increased plasma cortisol, increased cortisol-binding globulin, decreased dehydroepiandrosterone sulfate (DHEAS) levels), 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 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 30.

If pregnancy occurs during use of oral contraceptives, the drug should be discontinued immediately.

There is no convincing evidence 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 30, 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.

The use of combined oral contraceptives is generally not recommended until complete weaning.

Ability to influence reaction speed when driving or operating machinery

Lindinet 30 has no effect or a negligible effect on the ability to drive or operate machinery.

Method of Administration and Dosage

For oral use only.

The tablets should be taken daily at approximately the same time each day, 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. This should be followed by a 7-day tablet-free interval. During this 7-day interval, a withdrawal bleed similar to menstruation is expected. 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, the patient should start taking tablets from the next pack, which contains 21 tablets.

Starting Lindinet 30 for the first time

Lindinet 30 should be started on the first day of the menstrual cycle.

Tablets may also be started 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 30 from another combined hormonal contraceptive (combined oral contraceptives /COCs/, vaginal ring, or transdermal patch)

The first tablet of Lindinet 30 should be taken the day after the last active tablet of the previous combined oral contraceptive, but no later than the day after the usual tablet-free interval (or placebo tablet) of the previous oral contraceptive pack.

When switching from a vaginal ring or transdermal patch to Lindinet 30, it is recommended to start taking Lindinet 30 on the day of removal of the vaginal ring or transdermal patch, but no later than the day the next ring or patch would have been applied.

Switching to Lindinet 30 from a progestogen-only contraceptive (‘mini-pill’, injection, implant, or intrauterine system)

Discontinuation of progestogen-only pills can occur at any time; Lindinet 30 should be started the following day. Switching from an implant or intrauterine system to Lindinet 30 can occur on the day of removal of the implant or intrauterine system. When switching from an injectable contraceptive, Lindinet 30 should be started on the day the next injection would have been administered. In all these cases, additional contraceptive methods should be used for the first 7 days.

Use of Lindinet 30 after first-trimester abortion

Lindinet 30 may be started immediately after a first-trimester abortion; in this case, additional contraceptive methods are not required.

Use of Lindinet 30 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 30 should not be started earlier than 28 days after childbirth in women who are not breastfeeding, or after second-trimester abortion. The woman should be advised to use an additional non-hormonal backup contraceptive method for the first 7 days of tablet intake. However, if sexual intercourse has already occurred after childbirth or abortion, pregnancy must be ruled out before starting Lindinet 30, or the woman should wait until the onset of the first menstrual period (see also sections "Special precautions" and "Use during pregnancy or breastfeeding").

Missed tablet

If a tablet is missed by less than 12 hours, 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 is more than 12 hours, contraceptive protection may be reduced. In this case, two main rules should be followed:

1. The tablet-free interval must never exceed 7 days.
2. Adequate suppression of the hypothalamic-pituitary-ovarian axis 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. Then continue taking tablets at the usual time. Additionally, a barrier method of contraception (e.g., condoms) 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 greater the number of missed tablets and the closer the missed tablet 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 must be taken at the same time. Then continue taking tablets at the usual time. If tablets were taken correctly for the 7 days prior to the missed tablet, 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 for the 7 days before the missed tablet. 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 must be taken at the same time. Then 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. Withdrawal bleeding is unlikely before the end of 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 the next pack should be started. If the woman wishes to start the next pack on her usual start date, the 7-day tablet-free interval should be shortened accordingly.

If withdrawal bleeding does not occur during the first usual tablet-free interval after missed tablets, pregnancy should be considered.

Actions to take in case of vomiting and/or diarrhea

If vomiting or diarrhea occurs within 4 hours of taking the tablet, the active ingredient may not have been completely absorbed. In this case, follow the instructions under "Missed tablet". If the patient wishes to maintain the regular dosing schedule, the missed tablets should be taken from a spare pack.

Delaying or advancing menstruation

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 completion of the second pack. During this time, spotting or breakthrough bleeding may occur. Regular use of Lindinet 30 can be resumed after a standard 7-day tablet-free interval.

To advance the onset of menstruation, 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 the next pack.

Children

Lindinet 30 is indicated for use only after regular menstruation has been established.

Overdose

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

Adverse Reactions

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

• Arterial and venous thrombotic and thromboembolic complications* (frequency: rare) (see also section "Special Warnings and 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 artery embolism. Detailed information on these adverse reactions is provided in the section "Special Warnings and 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 (≥1/10,000 to <1/1000), very rare (<1/10,000), 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)

Rare: hepatocellular carcinoma.

Immune system disorders

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

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.

Rare: exacerbation of chorea.

Eye disorders

Uncommon: intolerance to contact lenses.

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.

Rare: pancreatitis, ischemic colitis.

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

Hepatobiliary disorders

Uncommon: cholestatic jaundice.

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: change in body weight (increase or decrease).

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

Rare: decreased plasma folate levels*.

*Plasma lipid levels 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 vision loss.

***The use of combined oral contraceptives may worsen pre-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 induce or exacerbate angioedema symptoms.

In five studies comparing the risk of breast cancer in ever-users of COCs (current or past use) versus never-users, no association was found between COC use (ever use) and breast cancer risk, with effect estimates ranging from 0.90 to 1.12.

In three studies comparing the risk of breast cancer in current or recent users of COCs (<6 months since last use) versus never-users, one study found no association between COC use and breast cancer risk. The other two studies found a relative risk increase of 1.19–1.33 in current or recent users. Both studies observed an increased risk of breast cancer in women who used COCs for prolonged periods, with relative risks ranging from approximately 1.03 for less than one year of use to about 1.4 for more than 8–10 years of 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").

Data on suspected adverse reactions

Reporting suspected adverse reactions after product authorization is important. It 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 the reach of children.

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

Prescription category. Prescription only.

Manufacturer. Gedeon Richter Plc.

Manufacturer's address and location of operations.

H-1103 Budapest, Dózsa György út 19-21, Hungary.

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

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