Naadin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NAADINE (NAADINE)

Composition:

Active substances: ethinylestradiol, dienogest;

One coated tablet contains 2 mg dienogest and 0.03 mg ethinylestradiol;

Excipients: povidone; pregelatinized starch; lactose monohydrate; magnesium stearate; Opadry II White 85F18422 (polyethylene glycol, titanium dioxide (E 171), polyvinyl alcohol, talc).

Pharmaceutical form. Coated tablets.

Main physicochemical characteristics: cylindrical, biconvex, coated tablets of white color.

Pharmacotherapeutic group. Hormonal contraceptives for systemic use.

ATC code G03A A16.

Pharmacological properties

Pharmacodynamics

All hormonal contraceptive methods are characterized by a very low rate of contraceptive failure when used according to instructions. The rate of contraceptive failure may be higher if they are not used in accordance with instructions (e.g., missed tablet).

In clinical studies conducted with the combination ethinylestradiol/dienogest, the following Pearl Index was calculated:

Unadjusted Pearl Index: 0.454 (upper 95% confidence interval [CI]: 0.701);

Adjusted Pearl Index: 0.182 (upper 95% confidence interval: 0.358).

NAADIN is a combined oral contraceptive (COC) containing ethinylestradiol and the progestogen dienogest.

The contraceptive effect of NAADIN is based on the interaction of several factors, the most important of which are suppression of ovulation and changes in cervical secretion.

Dienogest is a derivative of nortestosterone with an in vitro affinity for progesterone receptors that is 10–30 times lower than that of other synthetic progestogens. In vivo data in animals indicate strong progestogenic and antiandrogenic activity. Dienogest does not exhibit significant androgenic, mineralocorticoid, or glucocorticoid activity in vivo.

The dose of dienogest required to suppress ovulation is 1 mg/day.

The use of high-dose COCs (50 mcg ethinylestradiol) reduces the risk of endometrial and ovarian cancer. Whether this also applies to low-dose COCs remains unclear.

Pharmacokinetics

Ethinylestradiol

Absorption

After oral administration, ethinylestradiol is rapidly and completely absorbed. Peak serum concentration is approximately 67 pg/mL and is reached within 1.5–4 hours. During absorption and first-pass metabolism in the liver, ethinylestradiol undergoes extensive metabolism, resulting in a mean oral bioavailability of approximately 44%.

Distribution

Ethinylestradiol is strongly, but non-specifically, bound to serum albumin (approximately 98%) and induces an increase in serum concentrations of sex hormone-binding globulin (SHBG). The apparent volume of distribution of ethinylestradiol is approximately 2.8–8.6 L/kg.

Metabolism

Ethinylestradiol undergoes presystemic conjugation in the intestinal mucosa and in the liver. Ethinylestradiol is metabolized primarily via aromatic hydroxylation, but a large number of hydroxylated and methylated metabolites are also formed, including both free metabolites and conjugates with glucuronides and sulfates. Clearance is 2.3–7 mL/min/kg.

Elimination

Serum levels of ethinylestradiol decline in a biphasic manner, with half-lives of approximately 1 hour and 10–20 hours, respectively. Ethinylestradiol is not excreted unchanged; its metabolites are excreted in urine and bile in a ratio of 4:6. The half-life of metabolites is approximately 1 day.

Steady state

Steady state is achieved during the second half of the treatment cycle, when serum concentrations of ethinylestradiol are approximately twice as high as after a single dose.

Dienogest

Absorption

After oral administration, dienogest is rapidly and completely absorbed. Peak serum concentration is reached within 2.5 hours after a single oral dose and is 51 ng/mL. The bioavailability of dienogest in combination with ethinylestradiol is approximately 96%.

Distribution

Dienogest binds to serum albumin and does not bind to SHBG or corticosteroid-binding globulin (CBG). Only 10% of the total dienogest concentration in serum is present as free steroid, while 90% is non-specifically bound to albumin. The ethinylestradiol-induced increase in SHBG levels does not affect the protein binding of dienogest to serum proteins. The apparent volume of distribution of dienogest ranges from 37 to 45 L.

Metabolism

Dienogest is completely metabolized, primarily via hydroxylation and conjugation, resulting in inactive metabolites. These metabolites are rapidly eliminated from plasma such that no active metabolites are detectable in plasma, only unchanged dienogest. Total clearance is approximately 3.6 L/h after a single dose.

Elimination

Serum levels of dienogest decline with a half-life of 9 hours. Only a negligible amount of dienogest is excreted unchanged by the kidneys.

After administration of an oral dose of 0.1 mg/kg body weight, the ratio of renal to fecal excretion is 3.2. Approximately 86% of the administered dose is excreted within 6 days, with the majority (42%) excreted in urine within the first 24 hours.

Steady state

The pharmacokinetics of dienogest are independent of SHBG levels. With daily administration, serum concentrations increase 1.5-fold, reaching steady state after 4 days of treatment.

Safety preclinical data

Preclinical studies with ethinylestradiol and dienogest revealed the expected estrogenic and progestogenic effects.

Results from standard preclinical studies on repeated-dose toxicity, genotoxicity, carcinogenicity, and reproductive toxicity do not indicate any specific risk for humans. However, it should be noted that sex steroids may promote the growth of pre-existing hormone-dependent tissues and tumors.

Clinical characteristics.

Indications.

Oral contraception.

Contraindications.

Combined hormonal contraceptives (CHCs) must not be used if any of the conditions or diseases listed below are present. If any of these conditions or diseases develops for the first time during use, the product should be discontinued immediately.

Presence of or risk of venous thromboembolism (VTE)

Current venous thromboembolism (during anticoagulant therapy) or history of venous thromboembolism (e.g., deep vein thrombosis (DVT), pulmonary embolism (PE));

known hereditary or acquired predisposition to venous thromboembolism, such as activated protein C resistance (including factor V Leiden mutation), antithrombin III deficiency, protein C deficiency, protein S deficiency;

major surgery with prolonged immobilization (see section "Special precautions");

high risk of venous thromboembolism due to the presence of multiple risk factors (see section "Special precautions");

Presence of or risk of arterial thromboembolism (ATE)

arterial thromboembolism – current or past history of arterial thromboembolism (e.g., myocardial infarction) or presence of prodromal symptoms (e.g., angina pectoris);

current or past history of cerebrovascular accident, or presence of prodromal symptoms (e.g., transient ischemic attack (TIA));

known hereditary or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinemia and antiphospholipid antibodies (anti-cardiolipin antibodies, lupus anticoagulant);

history of migraine with focal neurological symptoms;

high risk of arterial thromboembolism due to the presence of multiple risk factors (see section "Special precautions") or due to the presence of a single serious risk factor such as:

diabetes mellitus with vascular complications;

severe arterial hypertension;

severe dyslipoproteinemia;

current or past history of pancreatitis, if associated with severe hypertriglyceridemia.

• Severe liver disease until liver function tests return to normal.
• Current or past history of liver tumors (benign or malignant).
• Known or suspected hormone-dependent malignant neoplasms (e.g., of genital organs or breasts).
• Vaginal bleeding of unknown etiology.
• Established or suspected pregnancy.
• Hypersensitivity to the active substances or to any of the excipients of the product.

Interaction with other medicinal products and other forms of interaction.

Note: Information regarding the concurrently used medicinal product should be consulted to identify potential interactions.

Effect of other medicinal products on NAADIN

Interactions are possible with medicinal products that induce microsomal enzymes. This may lead to increased clearance of sex hormones, which in turn may result in changes in the pattern of menstrual bleeding and/or loss of contraceptive efficacy.

Therapy

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

Short-term treatment

Women taking enzyme-inducing medicinal products should temporarily use a barrier method or another contraceptive method in addition to COCs. The barrier method should be used throughout the treatment period with the concomitant medicinal product and for an additional 28 days after discontinuation of the treatment. If treatment is initiated during the period of taking the last tablets of the COC pack, the next pack of COCs should be started immediately after completing the previous pack, without the usual tablet-free interval.

Long-term treatment

For women undergoing long-term therapy with enzyme-inducing substances, it is recommended to choose another reliable non-hormonal contraceptive method.

Substances that increase COC clearance (reduced COC efficacy due to enzyme induction), for example: barbiturates, carbamazepine, phenytoin, primidone, rifampicin; also possibly oxcarbazepine, topiramate, felbamate, griseofulvin, and medicinal products containing St. John's wort (Hypericum perforatum) extract.

Substances with variable effects on COC clearance

When used concomitantly with COCs, many combinations of HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors may increase or decrease plasma concentrations of estrogens or progestins. The overall effect of such changes may be clinically significant in some cases.

Therefore, the package leaflet of the medicinal product used for HIV/HCV treatment should be consulted to identify potential interactions. In case of any doubts, women should additionally use a barrier method of contraception during therapy with protease inhibitors or non-nucleoside reverse transcriptase inhibitors.

Substances that decrease COC clearance (enzyme inhibitors)

The clinical significance of potential interactions with enzyme inhibitors remains unclear.

Concomitant use of strong CYP3A4 inhibitors may increase plasma concentrations of estrogen, progestin, or both components.

Etoricoxib at doses of 60 to 120 mg/day has demonstrated a 1.4- to 1.6-fold increase in plasma concentrations of ethinylestradiol when administered concomitantly with a combined hormonal contraceptive containing 0.035 mg ethinylestradiol.

Effect of NAADIN on other medicinal products

CHCs may affect the metabolism of other medicinal products. Consequently, plasma and tissue concentrations may increase (e.g., cyclosporine) or decrease (e.g., lamotrigine). However, in vitro data indicate that inhibition of CYP enzymes by dienogest at therapeutic doses is unlikely.

Clinical data indicate that ethinylestradiol inhibits the clearance of CYP1A2 substrates, resulting in mild (e.g., with theophylline) or moderate (e.g., with tizanidine) increases in their plasma concentrations.

Other forms of interaction

Laboratory tests

The use of contraceptive steroids may affect the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal, and kidney function, plasma concentrations of binding proteins such as corticosteroid-binding globulin and lipid/lipoprotein fractions, carbohydrate metabolism parameters, as well as coagulation and fibrinolysis parameters. Such changes are usually within normal limits.

Special precautions.

The decision to prescribe NAADIN should be made taking into account risk factors, including risk factors for venous thromboembolism (VTE), as well as the risk of VTE associated with NAADIN compared to other combined oral contraceptives (COCs) (see sections "Contraindications" and "Special precautions").

Warning. If any of the conditions or risk factors listed below are present, the appropriateness of using NAADIN should be discussed with the woman.

Women should be advised to contact their physician if they experience an exacerbation or the first signs of any of these conditions or risk factors, and to determine whether discontinuation of NAADIN is necessary.

Oral contraceptives should be discontinued if suspected or confirmed VTE or arterial thromboembolism (ATE) occurs. If anticoagulant therapy is initiated, an alternative effective contraceptive method should be provided due to the teratogenic effects of anticoagulants (coumarins).

Circulatory disorders

Risk of venous thromboembolism (VTE)

The use of any COCs increases the risk of venous thromboembolism (VTE) in women who use them compared to women who do not. COCs containing levonorgestrel, norgestimate, or norethisterone are associated with the lowest risk of VTE. The risk associated with NAADIN compared to these lower-risk COCs is currently unknown. The decision to use a COC other than those with the lowest VTE risk should only be made after discussion with the woman. It is important to ensure that she understands the risk of VTE associated with COC use, the extent to which her individual risk factors contribute, and that the risk of VTE is highest during the first year of use. Some data suggest that the risk of VTE may increase when restarting COCs after a break of 4 weeks or longer.

Among 10,000 women who do not use COCs and are not pregnant, approximately 2 will develop VTE within one year. However, for any individual woman, the risk may be significantly higher depending on her individual risk factors (see below).

Epidemiological studies in women using low-dose COCs (< 50 µg ethinylestradiol) show that 6–12 out of 10,000 women will develop VTE within one year.

It is estimated that approximately 61 out of 10,000 women using COCs containing levonorgestrel will develop VTE within one year.

Limited epidemiological data suggest that the risk of VTE with COCs containing dienogest may be similar to that with COCs containing levonorgestrel.

The number of VTE cases per year mentioned above is lower than that expected during pregnancy or the postpartum period.

VTE can be fatal 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.

1 An average of 5–7 cases per 10,000 woman-years, based on calculated relative risk of COCs containing levonorgestrel compared to non-COC users (approximately 2.3–3.6 cases).

Risk factors for VTE

The risk of venous thromboembolic complications in women using COCs may be substantially increased in the presence of additional risk factors, especially multiple ones (see table).

NAADIN is contraindicated in women with multiple risk factors that may increase the 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 risks associated with each individual factor, so the overall risk of VTE should be considered. If the benefit-risk balance is unfavorable, COCs should not be prescribed (see section "Contraindications").

Table 1. Risk factors for VTE

Risk factor	Note
Obesity (body mass index over 30 kg/m²)	Risk increases significantly with increasing body mass index. Particular attention is required in the presence of other risk factors.
Long-term immobilization, major surgery, any surgery on lower limbs or pelvic organs, neurosurgical procedures, or extensive trauma. Note: temporary immobilization, including flights > 4 hours, may also be a risk factor for VTE, especially in women with other risk factors.	In such situations, it is recommended to discontinue the use of the drug (at least 4 weeks before planned surgery) and not resume use earlier than 2 weeks after full restoration of mobility. To prevent unwanted pregnancy, other contraceptive methods should be used. Consideration should be given to antithrombotic therapy if use of NAADIN had not been discontinued previously.
Family history (venous thromboembolism in a close relative or parent, especially at a relatively young age, e.g. before 50 years).	If hereditary predisposition is suspected, women should consult a specialist before using any COCs.
Other conditions associated with VTE	Cancer, systemic lupus erythematosus, hemolytic-uremic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis), and sickle cell anemia.
Age	Especially over 35 years of age.

There is no consensus regarding the possible influence of varicose veins and superficial thrombophlebitis on the occurrence or development of venous thromboembolism.

Particular attention should be paid to the increased risk of thromboembolism during pregnancy, especially within the 6 weeks following delivery (for information on pregnancy and breastfeeding, see section "Use during pregnancy or breastfeeding").

Signs and symptoms of VTE (deep vein thrombosis and pulmonary embolism)

Women should be advised to seek immediate medical attention and inform their physician that they are taking COCs if any of the following symptoms occur.

Symptoms of DVT may include:

• Unilateral swelling of the thigh, lower leg, and/or foot or along a vein in the leg;
• Pain or increased tenderness in the leg, which may occur only when standing or walking;
• A sensation of warmth in the affected leg;
• Redness or change in skin color of the leg.

Symptoms of PE may include:

• Sudden unexplained shortness of breath or rapid breathing;
• Sudden cough, possibly with hemoptysis;
• Sudden chest pain;
• Severe dizziness or lightheadedness;
• 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 manifestations of vascular occlusion may include sudden pain, swelling, and mild cyanosis of a limb.

Ocular vessel occlusion may initially present with painless blurred vision, which may progress to vision loss. In some cases, vision loss occurs almost immediately.

Risk of arterial thromboembolism (ATE)

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

Risk factors for ATE

The risk of arterial thromboembolic complications or cerebrovascular events increases in women using COCs who have risk factors (see table). The use of NAADIN is contraindicated in women who have either one serious or multiple risk factors for ATE that may increase the risk of arterial thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the risk increase may be greater than the sum of the risks associated with each individual factor, so the overall risk should be considered. COCs should not be prescribed if the benefit-risk ratio is unfavorable (see section "Contraindications").

Table 2. Risk factors for ATE

Increased age	Note
Increased age	Especially in women over 35 years of age
Smoking	Women using COCs are advised not to smoke. Women over 35 years of age who continue to smoke are strongly advised to use another method of contraception.
Arterial hypertension
Obesity (body mass index over 30 kg/m²)	Risk increases significantly with increasing body mass index. Requires particular attention when other risk factors are present in women.
Family history (arterial thromboembolism in a close relative or parent, especially at a relatively young age, e.g., under 50 years)	If hereditary predisposition is suspected, women are advised to consult a specialist before using any COCs.
Migraine	An increase in the frequency or severity of migraine during COC use (possible prodromal signs preceding cerebrovascular events) may necessitate immediate discontinuation of COCs.
Other conditions associated with adverse vascular reactions	Diabetes mellitus, hyperhomocysteinemia, cardiac valve disorders, atrial fibrillation, dyslipoproteinemia, and systemic lupus erythematosus.

Arterial thromboembolism (ATE) symptoms

Women should be advised to seek immediate medical attention and inform their doctor if any of the following symptoms occur while 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 disturbances, or difficulty understanding speech;

sudden worsening of vision in one or both eyes;

sudden, severe, or prolonged headache of unknown origin;

loss of consciousness or fainting, with or without seizures.

Transient nature of symptoms may indicate transient ischemic attack (TIA).

Symptoms of myocardial infarction may include:

pain, discomfort, pressure, heaviness, squeezing, or fullness in the chest, arm, or below the sternum;

discomfort radiating to the back, jaw, throat, arm, or stomach;

feeling of bloating, indigestion, or heartburn;

excessive sweating, nausea, vomiting, or dizziness;

extreme weakness, anxiety, or shortness of breath;

rapid or irregular heartbeat.

Tumors

Results of some epidemiological studies suggest an increased risk of cervical cancer with long-term use of COCs, although this remains controversial due to uncertainty about how much the results are influenced by confounding risk factors such as human papillomavirus infection.

A meta-analysis based on 54 epidemiological studies indicates a slight increase in relative risk (RR = 1.24) of breast cancer among women currently using COCs. This increased risk gradually returns to baseline age-related risk levels within 10 years after discontinuation of COCs. Since breast cancer is rare in women under 40 years of age, the additional number of diagnosed cases among current or recent COC users is small compared to the overall incidence of breast cancer. In rare cases, benign and even more rarely malignant liver tumors have been observed in women using COCs, which in some instances led to life-threatening intra-abdominal hemorrhage. In case of complaints of severe epigastric pain, hepatomegaly, or signs of intra-abdominal bleeding, the possibility of a liver tumor related to COC use should be considered in differential diagnosis.

Such neoplasms may be life-threatening or lead to fatal outcomes.

Other conditions

Women with hypertriglyceridemia or a family history of this disorder are at increased risk of pancreatitis when using COCs.

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 normotension is achieved with antihypertensive therapy. COCs should be discontinued if consistently high blood pressure values persist during COC use in women with pre-existing hypertension, despite adequate antihypertensive treatment.

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

In women with hereditary predisposition to angioedema, exogenous estrogens may induce or exacerbate angioedema symptoms.

COCs may need to be discontinued in cases of acute or chronic liver dysfunction until liver function parameters return to normal. COC use should be discontinued in case of recurrence of cholestatic jaundice that first occurred during pregnancy or previous use of sex hormones.

Although COCs may affect peripheral insulin resistance and glucose tolerance, there is no evidence requiring changes in therapeutic regimen for diabetic women taking low-dose COCs (< 0.05 mg ethinylestradiol). However, women with diabetes should be carefully monitored during COC use.

Depressed mood and depression are known adverse effects of hormonal contraceptives (see section "Adverse reactions"). Depression can be severe and is a known risk factor for suicidal behavior and suicide. Women should be advised to consult their doctor if they experience mood changes or depressive symptoms, including shortly after starting treatment.

Exacerbations of endogenous depression, epilepsy, Crohn’s disease, and ulcerative colitis have also been observed during COC use.

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

Each tablet contains 74.5 mg of lactose. In patients with rare hereditary conditions of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption, this lactose content should be taken into consideration.

Medical examination

Before initiating or resuming use of NAADIN, a complete medical and family history should be taken and pregnancy should be ruled out. Blood pressure should be measured and a medical examination performed, considering contraindications (see section "Contraindications") and special precautions (see section "Special precautions"). Women should be informed about venous and arterial thrombosis, including risks associated with NAADIN compared to other COCs, symptoms of VTE and ATE, known risk factors, and actions to take if thrombosis is suspected.

Patients should be advised to carefully read the package leaflet and follow its recommendations. The frequency and nature of follow-up examinations should be determined according to established treatment protocols and adapted to each individual woman.

Patients should be informed that NAADIN, like other combined oral contraceptives, does not protect against HIV infection (AIDS) or any other sexually transmitted diseases.

Reduced efficacy

The effectiveness of COCs may be reduced in case of missed tablets (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").

Cycle control

Irregular bleeding (spotting or breakthrough bleeding) may occur during COC use, especially during the first few months. Therefore, evaluation of irregular vaginal bleeding should only be performed after an adaptation period (usually after 3 cycles of tablet use).

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

In some women, withdrawal bleeding may not occur during the tablet-free interval. If COCs have been taken according to instructions (see section "Dosage and administration"), pregnancy is unlikely. However, if contraceptive use has been irregular or if withdrawal bleeding is absent for two consecutive cycles, pregnancy must be ruled out before continuing COC use.

Use during pregnancy or breastfeeding

Pregnancy

The drug is contraindicated during pregnancy. If pregnancy occurs during treatment, the drug should be discontinued immediately. However, epidemiological studies have not shown an increased risk of congenital malformations in children born to women who used COCs prior to pregnancy, nor evidence of teratogenic effects from inadvertent COC use in early pregnancy.

Animal studies have shown adverse effects during pregnancy (see section "Pharmacological properties"). Based on animal data, adverse effects due to hormonal influence of active substances cannot be excluded. However, extensive clinical experience with COC use during pregnancy does not indicate any adverse effects in humans.

When resuming NAADIN use, the increased risk of VTE in the postpartum period should be considered (see sections "Dosage and administration" and "Special precautions").

Breastfeeding

COCs may affect breastfeeding by reducing the quantity and altering the composition of breast milk. Active substances and/or their metabolites may pass into breast milk in small amounts, which may affect the infant. Therefore, COCs are not recommended during breastfeeding.

Ability to influence reaction speed when driving or operating machinery

No studies on the effect of the drug on the ability to drive or operate machinery have been conducted. No effects on the ability to drive or operate machinery have been observed in women using COCs.

Method of Administration and Dosage

For oral use.

The tablets should be taken daily according to the order indicated on the blister pack, approximately at the same time each day, with a small amount of liquid. The medication should be taken as 1 tablet per day for 21 consecutive days. The intake of tablets from the next pack should begin after the completion of the 7-day treatment-free interval, during which a withdrawal bleed usually occurs. Withdrawal bleeding typically starts on the 2nd or 3rd day after taking the last tablet and may not have ended before starting the next pack.

How to Start Treatment with NAADIN

• No previous hormonal contraceptives used (last month).

Treatment should begin on the first day of the natural cycle (i.e., the first day of menstrual bleeding).

• Switching from another combined oral contraceptive (COC)

It is advisable to start taking NAADIN the day after taking the last active (hormone-containing) tablet of the previous COC, but no later than the day after the tablet-free or placebo tablet interval of the previous COC.

• Switching from a vaginal ring or transdermal patch

It is advisable to start taking NAADIN on the day of removal of the vaginal ring or transdermal patch, but no later than the day when the next application of these products would have been due.

• Switching from a progestogen-only method (‘mini-pill’, injection, implant) or an intrauterine system containing progestogen.

Treatment can be started at any time after stopping the ‘mini-pill’ (in the case of an implant or intrauterine system – on the day of removal, in the case of an injection – instead of the next scheduled injection). However, in all cases, it is recommended to additionally use a barrier method of contraception during the first 7 days of taking NAADIN.

• After first-trimester abortion.

Treatment can be started immediately. In this case, there is no need to use additional contraceptive methods.

• After childbirth or second-trimester abortion.

For breastfeeding women, see section "Use during pregnancy or breastfeeding".

It is recommended to start treatment with NAADIN on days 21–28 after childbirth or second-trimester abortion. If treatment is started later, it is recommended to additionally use a barrier method of contraception during the first 7 days of taking NAADIN. However, if sexual intercourse has already occurred, pregnancy should be ruled out before starting treatment or wait for the onset of the first menstruation.

For women who are breastfeeding, see section "Use during pregnancy or breastfeeding".

What to Do in Case of Missed Tablet Intake

If the delay in taking the tablet does not exceed 12 hours, the contraceptive effect of the medication is not reduced. The missed tablet should be taken as soon as possible. The next tablet from the pack should be taken at the usual time.

If the delay in taking the missed tablet exceeds 12 hours, contraceptive protection may be reduced. In such cases, the following two main principles should be followed:

1. The interval between tablet intakes must never exceed 7 days.
2. Adequate suppression of the hypothalamic-pituitary-ovarian system is achieved by continuous tablet intake for 7 days.

Accordingly, in everyday practice, the following recommendations should be followed:

• Week 1

Take the last missed tablet 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., 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 doses are to the end of the pack, the higher the risk of pregnancy.

• Week 2

Take the last missed tablet as soon as possible, even if two tablets have to 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 dose, no additional contraceptive methods are required. Otherwise, or if more than one tablet is missed, it is recommended to additionally use a barrier method of contraception for 7 days.

• Week 3

The risk of reduced effectiveness increases as the tablet-free interval approaches. However, by following one of the regimens below, a reduction in contraceptive protection can be avoided, provided tablets were taken correctly for the 7 days before the missed dose. Otherwise, it is recommended to follow the first option below and use additional precautionary methods for the next 7 days.

1. Take the last missed tablet as soon as possible, even if two tablets have to be taken at the same time. Then continue taking tablets at the usual time. Tablets from the next pack should be started immediately after finishing the current pack, i.e., there should be no break between packs. It is unlikely that a withdrawal bleed will occur before finishing tablets from the second pack, although breakthrough bleeding or spotting may occur during treatment.
2. Alternatively, tablet intake from the current pack may be stopped. In this case, the tablet-free interval should not exceed 7 days, including the days of missed tablets; tablet intake should then resume from the next pack.

If the expected withdrawal bleed does not occur during the first normal tablet-free interval after missed tablets, pregnancy is possible. A doctor should be consulted before starting a new pack.

Recommendations in Case of Gastrointestinal Disorders

In case of severe gastrointestinal disorders, incomplete absorption of the medication is possible; therefore, additional contraceptive methods should be used. If vomiting occurs within 3–4 hours after taking a tablet, another tablet should be taken as soon as possible. If more than 12 hours have passed, the recommendations provided above in the section "Method of Administration and Dosage", subsection "What to Do in Case of Missed Tablet Intake", apply. If a woman does not wish to change her tablet-taking schedule, she should take an additional tablet(s) from the next pack.

How to Delay Withdrawal Bleeding

To delay withdrawal bleeding, continue taking NAADIN tablets from a new pack without a break. If desired, treatment may be continued until the end of the second pack. Breakthrough bleeding or spotting may occur during this time. Usually, treatment is resumed after a 7-day tablet-free interval.

To shift the timing of withdrawal bleeding to another day of the week, it is recommended to shorten the tablet-free interval by as many days as desired. It should be noted that the shorter the interval, the more frequently absence of withdrawal bleeding and breakthrough bleeding or spotting may occur during the intake of tablets from the second pack (similar to the case of delaying withdrawal bleeding).

Additional Information for Special Patient Groups

Geriatric patients

The medication is not indicated after menopause.

Patients with hepatic impairment

The medication is contraindicated in women with severe liver disease.

Patients with renal impairment

The use of the medication in patients with impaired kidney function has not been specifically studied. Available data do not indicate the need for dosage adjustment in this patient group.

Children

The medication is indicated for use only after the onset of menstruation.

Overdose

Acute toxicity of ethinylestradiol and dienogest following oral administration is very low. For example, if a child accidentally ingests several NAADIN tablets at once, symptoms of intoxication are unlikely. Possible symptoms in such cases include nausea, vomiting, and slight vaginal bleeding in young girls. Specific treatment is generally not required. If necessary, symptomatic therapy may be administered.

Adverse reactions.

The frequency of adverse reactions is summarized in the table below. Within each column, adverse reactions are listed in order of decreasing frequency. Frequency is defined as common (≥1/100 to ≤1/10), uncommon (≥1/1000 to <1/100), and rare (≥1/10,000 to <1/1000). Other adverse reactions for which frequency cannot be estimated are listed in the column "Frequency not known".

Table 3. Frequency of adverse reactions reported for the active substances in the drug NAADIN

System Organ Classes	Common	Uncommon	Rare	Frequency not known
Infections and infestations		vaginitis/vulvovaginitis, vaginal candidiasis or other fungal vulvovaginal infections	salpingo-oophoritis, urinary tract infections, cystitis, mastitis, cervicitis, fungal infections, candidiasis, oral herpes, influenza, bronchitis, sinusitis, upper respiratory tract infections, viral infections
Benign, malignant and unspecified neoplasms (including cysts and polyps)			uterine leiomyoma, breast lipoma
Blood and lymphatic system disorders			anemia
Immune system disorders			hypersensitivity
Endocrine disorders			virilization syndrome
Metabolism and nutrition disorders		increased appetite	anorexia
Psychiatric disorders		depressed mood	depression, mental disorders, insomnia, sleep disorders, aggression	mood changes, increased libido, decreased libido
Nervous system disorders	headache	dizziness, migraine	ischemic stroke, cerebral circulation disorder, dystonia
Eye disorders			dry eye mucosa, eye irritation, oscillopsia, vision disorders	contact lens intolerance
Ear and labyrinth disorders			sudden hearing loss, tinnitus, vertigo, hearing disorders
Cardiac disorders			cardiovascular disorders, tachycardia2
Vascular disorders		hypertension, hypotension	VTE, ATE, PTE, thrombophlebitis, diastolic hypertension, circulatory orthostatic disorders, hot flushes, varicose veins, venous disorders, venous pain
Respiratory, thoracic and mediastinal disorders			asthma, hyperventilation
Gastrointestinal disorders		abdominal pain3, nausea, vomiting, diarrhea	gastritis, enteritis, dyspepsia
Skin and subcutaneous tissue disorders		acne, alopecia, rash4, pruritus5	allergic dermatitis, atopic dermatitis/ neurodermatitis, eczema, psoriasis, hyperhidrosis, chloasma, pigmentation disorders/ hyperpigmentation, seborrhea, dandruff, hirsutism, skin disorders, skin reactions, cellulite ("orange peel" skin), spider angioma	urticaria, nodular erythema, multiform erythema
Musculoskeletal and connective tissue disorders			back pain, muscle and bone discomfort, myalgia, limb pain
Reproductive system and breast disorders	breast tenderness6	withdrawal bleeding abnormalities7, intermenstrual bleeding8, breast enlargement9, breast swelling, dysmenorrhea, genital/vaginal discharge, ovarian cyst, pelvic pain	cervical dysplasia, adnexal cyst, adnexal tenderness, breast cyst, fibrocystic mastopathy, dyspareunia, galactorrhea, menstrual disorders	breast discharge
General disorders		increased fatigue10	chest pain, peripheral edema, influenza-like illness, inflammation, pyrexia, irritability	fluid retention
Investigations		weight gain	elevated blood triglycerides, hypercholesterolemia, weight loss, weight changes
Congenital, familial and genetic disorders			asymptomatic polymastia manifestations

2 including increased heart rate

3 including upper and lower abdominal pain, abdominal discomfort/distension

4 including maculopapular rash

5 including generalized pruritus

6 including breast discomfort and tension

7 including menorrhagia, hypomenorrhea, oligomenorrhea, and amenorrhea

8 including vaginal bleeding and metrorrhagia

9 including breast tenderness and swelling

10 including weakness and malaise

The most appropriate MedDRA term has been used to describe each adverse reaction.

Synonyms or related conditions are not listed but should be taken into consideration.

Description of selected adverse reactions

The following serious adverse reactions have been observed in women using COCs (see also section "Special warnings").

Tumours

• A slightly increased frequency of breast cancer diagnosis has been reported among women using oral contraceptives. Since breast cancer is rare in women under 40 years of age, the overall risk remains small. The relationship to COC use is not known.
• Liver tumours (benign and malignant).
• Cervical cancer.

Other conditions

• Hypertriglyceridaemia (increased risk of pancreatitis with COC use).
• Arterial hypertension.
• Development or exacerbation of disorders for which a relationship with COC use has not been definitively established: jaundice and/or pruritus associated with cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham’s chorea; herpes gestationis; hearing loss associated with otosclerosis.
• In women with hereditary predisposition to angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.
• Disorders of liver function.
• Changes in glucose tolerance or effects on peripheral insulin resistance.
• Crohn’s disease, ulcerative colitis.
• Chloasma.

Interactions

Breakthrough bleeding and/or reduced contraceptive efficacy may occur due to interactions between other medicinal products (enzyme inducers) and oral contraceptives (see section "Interaction with other medicinal products and other forms of interaction").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions.

Shelf life.

2 years.

Storage conditions.

Keep out of the reach of children and store at temperatures not exceeding 25 °C.

Packaging.

21 film-coated tablets in a blister with calendar strip. 1 blister per cardboard box.

Prescription category.

Prescription only.

Manufacturer.

Cyndea Pharma, S.L.

Manufacturer's address.

Poligono Industrial Emiliano Revilla Sanz, Avenida de Agreda, 31, Olvega 42110 Soria, Spain.

Marketing Authorisation Holder.

Naari PTE. Limited.

Address of the Marketing Authorisation Holder.

36 Robinson Road #13-01, City House, Singapore 068877