Janine

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT JENINE® (JEANINE®)

Composition:

Active substances: ethinylestradiol, dienogest;

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

Excipients: lactose monohydrate, maize starch, maltodextrin, magnesium stearate, sucrose, glucose syrup, calcium carbonate, povidone K25, macrogol 35000, carnauba wax, titanium dioxide (E 171).

Pharmaceutical form. Coated tablets.

Main physicochemical properties: shiny white coated tablets.

Pharmacotherapeutic group. Hormonal contraceptives for systemic use. Progestogens and estrogens, fixed combinations. Dienogest and ethinylestradiol.

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 contraceptive failure rate may be higher if contraceptives are not used in accordance with instructions (e.g., missed tablet intake).

During clinical trials conducted with the medicinal product Janine®, the Pearl Index was calculated as follows:

• Unadjusted Pearl Index: 0.454 (upper 95% confidence interval [CI]: 0.701);
• Adjusted Pearl Index: 0.182 (upper 95% confidence interval: 0.358).

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

The contraceptive effect of Janine® 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.

When high-dose COCs (50 mcg ethinylestradiol) are used, the risk of endometrial and ovarian cancer is reduced. 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 an average 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 pre-systemic conjugation in the mucosa of the small intestine 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 one day.

Steady state. Steady state is achieved during the second half of the cycle of use, when serum concentrations of ethinylestradiol are approximately twice as high as those observed 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 of Janine® and is 51 ng/mL. The absolute 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. The apparent volume of distribution of dienogest ranges from 37 to 45 L.

Metabolism. Dienogest is metabolized primarily via hydroxylation and conjugation, forming mainly endocrinologically 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 single administration.

Elimination. Serum levels of dienogest decline with a half-life of approximately 9 hours. Only a small 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 by a factor of 1.5, reaching steady state after 4 days of use.

Safety preclinical data

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

Results from standard preclinical studies on repeat-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.

Environmental risk assessment studies have shown that ethinylestradiol and dienogest may potentially pose a threat to the aquatic environment (see section "Special precautions for environmental safety").

Clinical characteristics.

Indications.

Oral contraception.

Contraindications.

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

• Presence or risk of venous thromboembolism (VTE)
  • Current (during anticoagulant therapy) or past 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 presence of multiple risk factors (see section "Special precautions").
• Presence 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 presence of multiple risk factors (see section "Special precautions") or due to presence of a single serious risk factor such as:
    • diabetes mellitus with vascular complications;
    • severe arterial hypertension;
    • severe dyslipoproteinemia.
• Acute or past history of pancreatitis, if associated with severe hypertriglyceridemia.
• Severe liver disease, current or past, until liver function tests return to normal limits.
• Current or past history of liver tumors (benign or malignant).
• Known or suspected hormone-dependent malignant neoplasms (e.g., of genital organs or mammary glands).
• Established or suspected pregnancy.
• Vaginal bleeding of unknown etiology.
• Hypersensitivity to the active substances or to any of the excipients of the medicinal product.

The medicinal product Janine® is contraindicated when used concomitantly with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, or with medicinal products containing glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction").

Special precautions.

This medicinal product may pose a hazard to the environment (see section "Pharmacological properties"). Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Interaction with other medicinal products and other forms of interaction.

Note: Information regarding any concurrently administered medicinal product should be reviewed to identify potential interactions.

Effect of other medicinal products on Janine®

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 starting treatment. Maximum enzyme induction generally occurs 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 use a barrier method or another contraceptive method in addition to COCs. The barrier method should be used throughout the duration of treatment with the relevant medicinal product and for an additional 28 days after discontinuation. If treatment is initiated during the period of taking the last tablets from the COC pack, the next pack of COCs should be started immediately after finishing the previous pack, without the usual tablet-free interval.

Long-term treatment

Women undergoing long-term therapy with enzyme-inducing active substances are advised to choose another reliable non-hormonal contraceptive method.

Active substances that increase COC clearance (reducing COC efficacy via 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).

Active substances with variable effects on COC clearance

When used concomitantly with COCs, numerous 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 contraceptive method during therapy with protease inhibitors or non-nucleoside reverse transcriptase inhibitors.

Active 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 1.4–1.6-fold increase in ethinylestradiol plasma concentrations, respectively, when co-administered with a combined hormonal contraceptive containing 0.035 mg ethinylestradiol.

Effect of Janine® on other medicinal products

COCs 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 suggest 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., theophylline) or moderate (e.g., tizanidine) increases in their plasma concentrations.

Pharmacodynamic interactions

During clinical trials involving patients receiving treatments for hepatitis C virus (HCV) infection containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, elevations in transaminases (ALT) greater than 5 times 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, in patients receiving treatment with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, increased ALT levels were observed in women taking ethinylestradiol-containing medicinal products, such as CHCs (see section "Contraindications").

Therefore, women using the medicinal product Janine® must use an alternative method of contraception (e.g., progestogen-only contraceptives or non-hormonal methods) prior to initiating therapy with the specified combination of medicinal products. Use of Janine® may be resumed 2 weeks after completion of therapy with the specified combination.

Other forms of interaction

Laboratory tests

Use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and kidney function, plasma concentrations of carrier proteins such as SHBG, lipid/lipoprotein fractions, carbohydrate metabolism parameters, and coagulation and fibrinolysis parameters. These changes are usually within normal limits.

Special precautions.

The decision to prescribe the medicinal product Yaz® should be made taking into account risk factors, including risk factors for venous thromboembolism (VTE), as well as the risk of VTE associated with the use of Yaz® 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 Yaz® should be discussed with the woman. In case of exacerbation or at the first signs of any of these conditions or risk factors, women are advised to consult a physician to determine whether discontinuation of Yaz® is necessary.

If suspected or confirmed venous or arterial thromboembolism (VTE or ATE) occurs, COCs should be discontinued. If anticoagulant therapy is initiated, an alternative adequate method of contraception should be provided due to the teratogenic effects of anticoagulants (coumarins).

• Circulatory disorders

Risk of venous thromboembolism (VTE)

The use of any COC increases the risk of VTE in women taking them compared to women who do not use COCs. Medicinal products containing levonorgestrel, norgestimate, or norethisterone are associated with the lowest risk of VTE. Use of other medicinal products, such as Yaz®, may increase the risk of VTE by a factor of 1.6. The decision to use a medicinal product 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 the use of Yaz®, the extent of influence of her individual risk factors, and the fact that the risk of VTE is highest during the first year of use. According to some data, the risk of VTE may increase when restarting COC use 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 1 year. However, for each 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) have shown that 6–12 out of 10,000 women will develop VTE within 1 year.

It is estimated that among 10,000 women using low-dose COCs containing levonorgestrel, approximately 6–7 will develop VTE within 1 year.

It is estimated\2, that among 10,000 women using low-dose COCs containing drospirenone and ethinylestradiol, 8–11 will develop VTE within 1 year.

The annual incidence of VTE is lower than that expected during pregnancy or the postpartum period.

VTE can be fatal in 1–2% of cases.

1On average 5–7 cases per 10,000 woman-years, based on calculated relative risk of COC use containing levonorgestrel compared to women not using COCs (approximately 2.3–3.6 cases).

2According to meta-analysis data, the risk of VTE in women using Yaz® is slightly higher compared to women using COCs containing levonorgestrel (RR = 1.57, 95% CI: 1.07–2.30).

Number of VTE cases per 10,000 women per year

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

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 1).

Yaz® 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; therefore, the overall risk of VTE should be considered. If the benefit-risk ratio is unfavorable, COCs should not be prescribed (see section "Contraindications").

Table 1. Risk factors for VTE

| Risk Factor | Comments | |-------------|----------| | Obesity (BMI > 30 kg/m²) | The risk of VTE increases with increasing BMI. | | Family history of VTE | Especially if it occurred at a young age (e.g., < 50 years) in a close relative (parent, sibling). This may indicate a hereditary predisposition. If such a predisposition is suspected or confirmed, further investigation is recommended before using COCs. | | Age over 35 years | The risk of VTE increases with age. | | Prolonged immobilization | Such as bed rest, major surgery, lower limb plaster casts, or long-haul flights (> 4 hours), especially in the presence of other risk factors. | | Smoking | Risk increases with age and number of cigarettes smoked. | | Medical conditions associated with VTE | Including hyperhomocysteinemia, antiphospholipid antibodies, factor V Leiden, prothrombin gene mutation, protein C or S deficiency, antithrombin deficiency. | | Other medical conditions | Such as systemic lupus erythematosus, hemolytic-uremic syndrome, chronic inflammatory bowel disease (Crohn’s disease, ulcerative colitis), sickle cell disease. | | Hypertension | Increases risk of arterial thrombosis. | | Dyslipidemia | May contribute to thrombotic risk. | | Migraine with aura | Increases risk of arterial thrombosis. | | History of VTE | Absolute contraindication to COC use. | | Known thrombophilic disorders | Absolute contraindication. |

Note: The presence of multiple risk factors significantly increases the overall risk. A careful assessment of benefit versus risk is essential before initiating Yaz®.

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

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

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 symptoms listed below occur.

Symptoms of DVT may include:

• Unilateral swelling of the thigh, calf, 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 on the leg.

Symptoms of PE may include:

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

Ocular vessel occlusion may initially present as painless blurred vision, which may progress to vision loss. Sometimes, vision loss develops almost immediately.

Risk of arterial thromboembolism (ATE)

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

Risk factors for ATE

When using COCs, the risk of developing arterial thromboembolic complications or cerebrovascular events increases in women with risk factors (see Table 2). The use of the medicinal product Janine® is contraindicated in women who have 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 overall risk increase may be greater than the sum of the risks associated with each individual factor, so the total risk should be considered. If the benefit-risk ratio is unfavorable, COCs should not be prescribed (see section "Contraindications").

Table 2. Risk factors for ATE

Symptoms of ATE

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

Symptoms of cerebrovascular disorders may include:

• sudden numbness or weakness of the face, arm, or leg, especially on one side of the body;
• sudden trouble 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 nature of these symptoms may indicate a transient ischemic attack (TIA).

Symptoms of myocardial infarction may include:

• chest pain, discomfort, heaviness, tightness, or pressure in the chest, arm, or below the sternum;

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

• feeling of fullness, indigestion, or choking;

• excessive sweating, nausea, vomiting, or dizziness;

• unusual 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; however, this observation remains controversial, as it is not fully established to what extent study results account for confounding risk factors such as sexual behavior and other factors, including 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 using COCs. This increased risk gradually returns to the baseline age-related risk level within 10 years after discontinuation of COCs. Since breast cancer is rare in women under 40 years of age, the increase in diagnosed cases among current or recent users of COCs is minimal in relation to the overall risk of breast cancer.

Benign, and in rare cases malignant, liver tumors have been observed in women using 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 COC-related liver tumor should be considered in differential diagnosis.

Such neoplasms may be life-threatening or result in 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 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 despite adequate antihypertensive treatment in women with pre-existing hypertension diagnosed prior to COC use. Cases of occurrence or worsening of the following conditions have been reported during pregnancy and COC use, but their causal relationship with COC use has not been definitively established: jaundice and/or pruritus associated with 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 and acquired angioedema.

COC use may need to be discontinued in cases of acute or chronic liver dysfunction until liver function tests return to normal. COCs should be discontinued in case of recurrence of cholestatic jaundice and/or pruritus associated with cholestasis 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 to suggest a need to alter the therapeutic regimen in women with diabetes mellitus taking low-dose COCs (< 0.05 mg ethinylestradiol). However, women with diabetes should be carefully monitored during COC use, especially at the beginning of treatment.

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

Psychiatric disorders

Depressed mood and depression are well-known adverse reactions that may occur during use of hormonal contraceptives (see section "Adverse reactions"). Depression can be a serious condition and is a well-known risk factor for suicidal behavior and suicide. Women should be advised to seek medical advice if they experience mood changes or symptoms of depression, including shortly after initiating treatment.

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.

Medical examination/consultation

Before initiating or resuming use of the medicinal product Janine®, a complete medical history (including family history) should be taken and pregnancy excluded. Blood pressure should be measured and a medical examination performed, taking into account contraindications (see section "Contraindications") and special precautions for use (see section "Special precautions for use"). Women should be informed about venous and arterial thrombosis, including the risk associated with use of Janine® compared to other COCs, symptoms of VTE and ATE, known risk factors, and actions to take if thrombosis is suspected.

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

Patients should be informed that hormonal contraceptives do not protect against HIV infection (AIDS) or any other sexually transmitted infections.

Reduced efficacy

The efficacy 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 disturbances

Irregular bleeding (spotting or breakthrough bleeding) may occur when using any COC, particularly during the first few months of use. Therefore, evaluation of any irregular bleeding should only be conducted after an adaptation period (usually after three cycles of use).

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

In some women, withdrawal bleeding may not occur during the drug-free interval. If COCs have been taken according to the recommendations in the section "Dosage and administration," pregnancy is unlikely. However, if COCs have been taken irregularly before the first missed withdrawal bleed, or if two withdrawal bleeds are missed, pregnancy must be excluded before continuing COC use.

Excipients

This medicinal product contains lactose, glucose, and sucrose. Women with rare hereditary problems of galactose intolerance, fructose intolerance, total lactase deficiency, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency should not take this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy. The medicinal product is not indicated during pregnancy.

If pregnancy occurs during use of Janine®, treatment should be discontinued immediately. Results of extensive epidemiological studies do not indicate an increased risk of congenital malformations in children whose mothers used COCs prior to pregnancy, nor evidence of teratogenic effects from inadvertent COC use during pregnancy.

Animal studies have shown adverse effects during pregnancy or breastfeeding (see section "Pharmacological properties"). Based on animal data, adverse effects due to the hormonal influence of the active substances cannot be excluded. However, overall clinical experience with COC use during pregnancy does not indicate any adverse effects in humans. When resuming use of Janine®, the increased risk of VTE in the postpartum period should be considered (see sections "Dosage and administration" and "Special precautions for use").

Breastfeeding. COCs may affect breastfeeding by reducing the quantity and altering the composition of breast milk. Small amounts of contraceptive steroids and/or their metabolites may pass into breast milk during COC use, and these amounts may affect the infant. Therefore, Janine® is not recommended for use until complete cessation of breastfeeding.

Ability to influence reaction speed when driving or operating machinery.

No studies on the effect on the ability to drive or operate machinery have been conducted.

No effect on the ability to drive or operate machinery has been observed in women using COCs.

Method of Administration and Dosage

For oral use.

Dosing

How to take the medicinal product Janine®

Take 1 tablet daily at approximately the same time every day, swallowing with a small amount of liquid if necessary, following the order indicated on the blister pack. Take 1 tablet/day for 21 consecutive days. After the 7-day break during which withdrawal bleeding usually occurs, start taking tablets from the next pack. Withdrawal bleeding typically begins on the 2nd or 3rd day after taking the last tablet and may continue until the start of the next pack.

How to start treatment with Janine®

• No previous use of hormonal contraceptives (in the preceding month)

Begin taking tablets 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 recommended to start taking Janine® tablets the day after the last active tablet of the previous COC, but no later than the day after the usual tablet-free interval or after taking the placebo tablets of the previous COC.

• Switching from a vaginal ring or transdermal patch

It is recommended to start taking Janine® 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

You may start taking Janine® 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 use an additional barrier method of contraception during the first 7 days of taking Janine®.

• After first-trimester abortion

Treatment with Janine® may 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 taking Janine® between days 21 and 28 after childbirth or second-trimester abortion. If treatment is started later, it is recommended to use an additional barrier method of contraception during the first 7 days of tablet intake. However, if sexual intercourse has already occurred, pregnancy should be ruled out before starting the COC, or wait for the onset of the first menstruation.

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

What to do if a tablet is missed

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

If the delay in taking the missed tablet exceeds 12 hours, contraceptive protection may be reduced. In this case, follow the two main rules:

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

Accordingly, the following practical 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. In addition, use a barrier method of contraception (e.g., condoms) for the next 7 days. If unprotected intercourse occurred in the previous 7 days, consider the possibility of pregnancy. The greater the number of missed tablets and the closer the missed dose is to the tablet-free interval, the higher the risk of pregnancy.

• Week 2

Take the last missed tablet 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 during the 7 days before the missed dose, no additional contraceptive methods are needed. However, if more than one tablet is missed, it is recommended to use additional contraceptive methods for 7 days.

• Week 3

The risk of reduced efficacy increases as the 7-day tablet-free interval approaches. However, by following one of the two regimens below, contraceptive protection can be maintained, provided tablets were taken correctly during the 7 days before the missed dose. Otherwise, follow the first option below and use additional contraceptive methods for the next 7 days.

1. Take the last missed tablet as soon as possible, even if two tablets must be taken simultaneously. Then continue taking tablets at the usual time. Start the next pack immediately after finishing the current one—there should be no break between packs. Withdrawal bleeding is unlikely before completing tablets from the second pack, although breakthrough bleeding or spotting may occur during this time.
2. Alternatively, stop taking tablets from the current pack. The tablet-free interval, including the days of missed tablets, should not exceed 7 days; then start taking tablets from the next pack.

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

Recommendations in case of gastrointestinal disorders

In case of severe gastrointestinal disturbances (e.g., vomiting or diarrhea), absorption of the drug may be incomplete; therefore, additional contraceptive methods should be used. If vomiting occurs within 3–4 hours after taking the tablet, take another tablet as soon as possible. If more than 12 hours have passed, follow the recommendations above under "What to do if a tablet is missed". If a woman does not wish to alter her tablet-taking schedule, she should take additional tablet(s) from the next pack.

How to delay withdrawal bleeding

To delay withdrawal bleeding, continue taking tablets from a new pack without interruption. The duration of intake may be extended up to the end of the second pack, if desired. Breakthrough bleeding or spotting may occur during this time. Resume regular use of Janine® after the usual 7-day tablet-free interval.

To shift the timing of withdrawal bleeding to another day of the week than that indicated by the current regimen, shorten the tablet-free interval by the desired number of days. Note that the shorter the interval, the more likely it is that withdrawal bleeding will not occur and the higher the risk of breakthrough bleeding or spotting during the next pack (similar to delaying withdrawal bleeding).

Additional information for special patient groups

• Elderly patients*

Do not use. Janine® is not indicated after menopause.

• Patients with hepatic impairment*

Janine® is contraindicated in women with severe liver disease. See also section "Contraindications".

• Patients with renal impairment*

Janine® has not been specifically studied in patients with renal impairment. Available data do not indicate the need for dosage adjustment in this patient group.

• Children*

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

Overdose

Acute toxicity of ethinylestradiol and dienogest after oral administration is very low. For example, if a child accidentally takes several tablets of Janine® at once, symptoms of intoxication are unlikely. Possible symptoms include nausea, vomiting, and withdrawal bleeding. Withdrawal bleeding may occur in girls even before menarche following accidental or unintentional intake of the drug. Specific treatment is generally not required. Symptomatic therapy may be administered if necessary.

Adverse reactions.

The frequency of adverse reactions reported during clinical trials of the medicinal product Yaz® (N=4942) in women taking the medicinal product as an oral contraceptive is summarized in Table 3. Within each frequency subgroup, adverse reactions are listed in order of decreasing severity. Frequency is defined as common (≥ 1/100 to ≤ 1/10), uncommon (≥ 1/1000 to < 1/100), and rare (≥ 1/10000 to < 1/1000). Other adverse reactions observed only during the post-marketing period, for which the frequency cannot be estimated, are listed under the subgroup "Frequency not known".

Table 3. Frequency of adverse reactions reported during clinical trials of the medicinal product Yaz®

3Including increased heart rate.

4Including upper and lower abdominal pain, abdominal discomfort/distension.

5Including macular rash.

6Including generalized pruritus.

7Including breast discomfort and tension.

8Including menorrhagia, hypomenorrhea, oligomenorrhea, and amenorrhea.

9Including vaginal bleeding and metrorrhagia.

10Including breast tenderness and swelling.

11Including 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 considered.

Description of individual adverse reactions

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

Tumours

• The frequency of breast cancer diagnosis is slightly increased in women using oral contraceptives. Since breast cancer is rare in women under 40 years of age, the overall frequency is small relative to the general risk of breast cancer. The relationship to COC use is unknown.
• Liver tumours (benign and malignant).
• Cervical cancer.

Other conditions

• Hypertriglyceridaemia (increased risk of pancreatitis with COC use).
• Arterial hypertension.
• Development or exacerbation of conditions whose relationship to COC use has not been definitively established: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham's chorea; herpes gestationis; hearing loss associated with otosclerosis.
• 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 decreased 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 marketing authorization is very important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions.

Shelf life.

3 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store in the original packaging to protect from light. Keep out of the reach of children.

Packaging.

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

Prescription category.

Prescription only.

Manufacturer.

Bayer Weimar GmbH & Co. KG.

Manufacturer's address.

Droemerstrasse 20, 99427 Weimar, Germany.