Denovel® 30

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DE NOVEL® 30

Composition:

Active substances: ethinylestradiol, dienogest;

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

Excipients: lactose monohydrate, maize starch, maltodextrin, magnesium stearate, white coating mixture for film coating (hypromellose, lactose monohydrate, titanium dioxide (E 171), macrogol 4000, sodium citrate).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, film-coated tablets without coating defects.

Pharmacotherapeutic group.

Hormonal contraceptives for systemic use. Progestogens and estrogens in combination. ATC code G03A A16.

Pharmacological Properties

Pharmacodynamics

All hormonal contraceptive methods are characterized by a very low contraceptive failure rate when used according to instructions. The contraceptive failure rate may be higher if contraceptives are not used as directed (e.g., missed tablet intake).

During clinical studies, 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% CI: 0.358).

Denovel**®** 30 is a combined oral contraceptive (COC) with antiandrogenic properties, containing ethinylestradiol and the progestogen dienogest.

The contraceptive effect of Denovel**®** 30 is based on the interaction of several factors, the most important of which are ovulation suppression 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. Maximum serum concentration (Cmax) 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 liver. It 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 elimination 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. Cmax is reached within 2.5 hours after a single oral dose 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 dienogest in serum is present as free steroid, while 90% is non-specifically bound to albumin. Ethinylestradiol-induced increases in SHBG levels do 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, so no active metabolites are detectable in plasma—only unchanged dienogest. Total clearance is approximately 3.6 L/hour after single administration.

Elimination. Serum levels of dienogest decline with an elimination half-life of approximately 9 hours. Only a negligible amount of dienogest is excreted unchanged in urine. After 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, plasma concentration increases by a factor of 1.5, reaching steady state after 4 days of use.

Preclinical safety data

Preclinical studies with ethinylestradiol and dienogest revealed 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 to 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.

The decision to prescribe Denovel®30 should take into account the current individual risk factors in women, particularly those related to venous thromboembolism (VTE), and the risk of VTE associated with the use of Denovel®30 compared to other combined hormonal contraceptives (CHCs) (see sections "Contraindications" and "Special precautions").

Contraindications.

COCs must not be used in the presence of any of the conditions listed below. If any of these conditions or diseases occurs for the first time during COC use, the drug should be discontinued immediately.

• Risk factors for venous thromboembolism (VTE):
  • Venous thromboembolism – current VTE (while on anticoagulant therapy) or history of VTE (e.g., deep vein thrombosis (DVT) or pulmonary embolism (PE));
  • Known hereditary or acquired predisposition to VTE, 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 VTE due to the presence of multiple risk factors (see section "Special precautions").
• Risk factors for arterial thromboembolism (ATE):
  • Arterial thromboembolism – current ATE, history of ATE (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 ATE, such as hyperhomocysteinemia and presence of antiphospholipid antibodies (anti-cardiolipin antibodies, lupus anticoagulant);
  • History of migraine with focal neurological symptoms;
  • High risk of ATE due to multiple risk factors (see section "Special precautions") or presence of a single risk factor such as:
  • Diabetes mellitus with vascular complications;
  • Severe hypertension;
  • Severe dyslipoproteinemia.
• Pancreatitis, including in history, if associated with severe hypertriglyceridemia.
• Current or past history of severe liver disease until liver function tests return to normal.
• Current or past history of liver tumors (benign or malignant).
• Known or suspected malignant neoplasms (e.g., of genital organs or breast) influenced by sex steroid hormones.
• Established or suspected pregnancy.
• Undiagnosed vaginal bleeding.
• Concomitant use 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").
• 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: To identify possible interactions, the package leaflets of all concomitantly used medicinal products should be consulted.

Effect of other medicinal products on Denovel®30

Interactions may occur with medicinal products that induce microsomal enzyme activity, which may lead to increased clearance of sex hormones and result in intermenstrual bleeding and/or loss of contraceptive efficacy.

Management strategy

Enzyme induction may be observed within a few days of treatment. Maximum enzyme induction is usually observed within several weeks. After discontinuation of the medication, 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 the COC. The barrier method should be used throughout the entire duration of treatment with the enzyme-inducing drug 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 COC tablets should be started immediately after completing the previous pack, without the usual tablet-free interval.

Long-term treatment

Women undergoing long-term treatment with enzyme-inducing substances are advised to use another reliable non-hormonal contraceptive method.

Substances that increase COC clearance (reducing COC efficacy via enzyme induction), e.g.:

barbiturates, carbamazepine, phenytoin, primidone, rifampicin, and possibly oxcarbazepine, topiramate, felbamate, griseofulvin, and products containing the herbal remedy St. John’s wort (Hypericum perforatum).

Substances with variable effects on COC clearance

When co-administered with COCs, many combinations of protease inhibitors and non-nucleoside reverse transcriptase inhibitors used in the treatment of HIV/viral hepatitis C may increase or decrease plasma concentrations of estrogen or progestin. In some cases, the net effect of these changes may be clinically significant.

Therefore, to identify possible interactions and provide appropriate recommendations, the prescribing information of concomitant medicinal products used for the treatment of HIV/viral hepatitis C should be consulted. In case of any doubt, women receiving a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor should use an additional barrier contraceptive method.

Substances that reduce COC clearance (enzyme inhibitors)

The clinical significance of potential interactions with enzyme inhibitors remains unknown. When strong inhibitors of CYP3A4 are co-administered, plasma concentrations of estrogen, progestin, or both may increase. Etoricoxib at doses of 60–120 mg/day has been shown to increase plasma concentrations of ethinylestradiol by 1.4–1.6 times, respectively, when co-administered with a CHC containing 35 mcg ethinylestradiol.

Effect of Denovel®30 on other medicinal products

COCs may affect the metabolism of other active substances. Consequently, plasma and tissue concentrations may increase (e.g., cyclosporine) or decrease (e.g., lamotrigine).

However, based on in vitro data, inhibition of CYP enzyme activity by dienogest at therapeutic doses is unlikely.

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

Other types of interactions

Laboratory tests

The use of contraceptive steroids may affect the results of certain laboratory tests, including liver, thyroid, adrenal, and kidney function biochemical parameters, plasma levels of protein carriers (e.g., corticosteroid-binding globulin), lipid/lipoprotein fractions, carbohydrate metabolism parameters, and coagulation and fibrinolysis parameters. Usually, changes remain within the normal laboratory reference ranges.

Pharmacodynamic interactions

During clinical trials in patients treated for hepatitis C virus (HCV) infection with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, alanine aminotransferase (ALT) levels increased significantly, exceeding the upper limit of normal (ULN) by 5 times. This elevation was more frequently observed in women using ethinylestradiol-containing products, particularly combined hormonal contraceptives (CHCs). Additionally, ALT elevation has also been observed when using antiviral medicinal products containing glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir in women taking ethinylestradiol-containing products such as CHCs (see section "Contraindications"). Therefore, patients taking Denovel**®30 should switch to an alternative contraceptive method (e.g., progestogen-only contraception or non-hormonal contraceptive methods) before initiating treatment with these combination regimens. Denovel®**30 may be resumed 2 weeks after completion of treatment with these combination regimens.

Special precautions for use.

Warning

If any of the conditions or risk factors listed below are present, the appropriateness of using Denovel**®** 30 should be discussed with the woman.

In the event of exacerbation or the first signs of any of these conditions or risk factors, women are advised to consult a physician to determine whether Denovel**®** 30 should be discontinued.

In case of suspected or confirmed venous thromboembolism (VTE) or arterial thromboembolism (ATE), combined oral contraceptives (COCs) should be discontinued. 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 developing VTE in women using them compared to women who do not use COCs. Preparations containing levonorgestrel, norgestimate, or norethisterone are associated with the lowest risk of VTE. The use of other medicinal products, such as Denovel® 30, may increase the risk of VTE by 1.6 times. The decision to use a product other than those with the lowest risk of VTE should only be made after discussing with the woman. It is important to ensure that she understands:

• the risk of VTE associated with the use of Denovel® 30;
• the extent to which her individual risk factors contribute;
• that the risk of VTE is highest during the first year of COC use. According to some data, the risk of VTE may increase when restarting COC use after a break of 4 weeks or longer.

Approximately 2 out of 10,000 women who do not use COCs and are not pregnant 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 mcg ethinylestradiol) have shown that 6–12 out of 10,000 women will develop VTE within one year.

According to estimates, approximately 6[1] out of 10,000 women using COCs containing levonorgestrel will develop VTE within one year.

It is estimated that 8–11[2] out of 10,000 women using COCs containing dienogest and ethinylestradiol will develop VTE within one year.

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

VTE can be fatal in 1–2% of cases.

Number of VTE cases per 10,000 women per year

Very rarely, thrombosis in other blood vessels (e.g., arteries and veins of the liver, kidneys, mesenteric vessels, or retinal vessels) has been reported in women using COCs.

Risk factors for VTE

The risk of venous thromboembolic complications in women using COCs may be significantly higher in the presence of additional risk factors, especially multiple ones (see Table 1).

The use of Denovel**®** 30 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 the risks associated with each individual factor, so 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		Comment
Obesity (body mass index exceeds 30 kg/m²)		Risk increases significantly with higher body mass index. Particular attention is required in the presence of other risk factors.
Prolonged immobilization, major surgery, any surgical intervention on lower limbs or pelvic organs, neurosurgical procedures, or extensive trauma. Note: temporary immobilization, including air travel lasting >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 elective surgery) and not resume its use earlier than 2 weeks after full restoration of mobility. Alternative contraceptive methods should be used to prevent unintended pregnancy. Consideration should be given to antithrombotic therapy if prior discontinuation of the drug did not occur.
	Family history (VTE at any time in siblings or parents, 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.
	Increasing age	Especially in patients aged 35 years and older.

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, and especially during the 6 weeks following childbirth (for information on pregnancy and lactation, see section "Use during pregnancy or breastfeeding").

Symptoms of VTE (DVT and PE)

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

Symptoms of deep vein thrombosis (DVT) may include:

• unilateral swelling of the thigh, calf, and/or foot or along a vein in the leg;
• pain or increased sensitivity in the leg, which may only be felt when standing or walking;
• sensation of warmth in the affected leg; redness or change in skin color of the leg.

Symptoms of pulmonary embolism (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 vascular occlusion may initially present as blurred vision without pain, which may progress to vision loss. In some cases, vision loss develops almost instantaneously.

Risk of arterial thromboembolism (ATE)

Epidemiological studies indicate that the use of any COC is associated with an increased risk of ATE (myocardial infarction) or cerebrovascular events (e.g., transient ischemic attack [TIA], stroke). Arterial thromboembolic events may 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 Denovel® 30 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 increase in risk may be greater than the sum of the risks associated with each individual factor, and therefore the overall 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

Increased age	Particularly in patients aged 35 years and older
Smoking	Women taking COCs are advised not to smoke. Women aged 35 years and older 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 any siblings or parents, 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.
Migraine	An increase in the frequency or severity of migraine during COC use (possible prodromal signs preceding cerebrovascular events) may require immediate discontinuation of COC use.
Other conditions associated with adverse vascular reactions.	Diabetes mellitus, hyperhomocysteinemia, cardiac valve disorders, atrial fibrillation, dyslipoproteinemia, and systemic lupus erythematosus.

Symptoms of ATE

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 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 comprehension disturbances;
• sudden vision disturbances in one or both eyes;
• sudden, severe or prolonged headache without apparent cause;
• loss of consciousness or fainting, with or without seizures.

Transient symptoms may indicate a 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;
• sensation of stomach fullness, indigestion, or heartburn;
• 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 or presence of human papillomavirus infection.

A meta-analysis based on 54 epidemiological studies indicates a slight increase in relative risk (RR = 1.24) of breast cancer in women using COCs. This increased risk gradually returns to the baseline age-related risk level within 10 years after discontinuation of COC use. Since breast cancer is rare in women under 40 years of age, the increase in the number of diagnosed cases among current or recent users of COCs is minimal in relation to the overall risk 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 have led to life-threatening intra-abdominal hemorrhage. In cases of severe epigastric pain, hepatomegaly, or signs of intra-abdominal bleeding, the possibility of a liver tumor associated with COC use should be considered during 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 represent a high-risk group for developing pancreatitis during COC use.

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, COCs should be discontinued and hypertension treated. If appropriate, COC use may be resumed after normalization of blood pressure with antihypertensive therapy. COC use should be discontinued if, despite adequate antihypertensive treatment, persistently high blood pressure values remain during COC use in women with pre-existing hypertension diagnosed prior to COC initiation.

The following conditions have been reported to occur or worsen during pregnancy and with COC use, although their causal relationship with 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.

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

COCs may need to be discontinued in cases of acute or chronic liver dysfunction until liver function tests return to normal. COC use 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 are no data indicating the need to alter therapeutic regimens in diabetic women 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 observed during COC use.

Mood deterioration and depression are well-known adverse reactions during use of hormonal contraceptives (see section "Adverse Reactions"). Depression can be severe and is a known risk factor for suicidal behavior and suicide. Women should contact their physician if they experience mood changes or depressive symptoms, including shortly after starting treatment.

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.

Denovel® 30 contains lactose and sodium.

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

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

Medical examination/consultation

Before initiating or resuming use of Denovel® 30, a complete medical and family history should be taken and pregnancy excluded. Blood pressure should be measured and a medical examination performed, considering contraindications (see section "Contraindications") and warnings (see section "Special Warnings and Precautions for Use"). Women should be informed about venous and arterial thrombosis, including the associated risk with Denovel® 30 compared to other COCs, as well as symptoms of VTE and ATE, known risk factors, and actions to take if thrombosis is suspected.

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

Women 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 with all COCs, especially during the first few months of use. Therefore, evaluation of any irregular bleeding should only be conducted after an adaptation period (usually after 3 cycles of tablet intake).

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 tumors or 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 the instructions in the section "Dosage and Administration," pregnancy is unlikely. However, if COCs were taken irregularly before the first missed withdrawal bleed, or if two withdrawal bleeds are missed, pregnancy must be excluded before continuing COC use.

Use during pregnancy or breastfeeding

The drug is contraindicated during pregnancy.

If pregnancy occurs, the drug must be discontinued immediately.

Epidemiological studies have not shown an increased risk of congenital malformations in children whose mothers took oral contraceptives before pregnancy, nor evidence of teratogenic effects from accidental use of oral contraceptives in early pregnancy.

Animal studies have shown adverse reactions during pregnancy and lactation. Given these animal data, adverse reactions due to active compounds cannot be excluded. However, overall clinical experience with COC use during pregnancy has not provided evidence of actual adverse effects in humans.

The increased risk of VTE in the postpartum period should be considered when resuming Denovel® 30 (see sections "Special Warnings and Precautions for Use" and "Dosage and Administration").

COCs may affect lactation, as they may reduce the quantity and alter the composition of breast milk. Small amounts of contraceptive steroids and/or their metabolites may be excreted in breast milk. These amounts may affect the infant. Therefore, Denovel® 30 is not recommended until complete cessation of breastfeeding.

Ability to influence reaction speed when driving vehicles or operating machinery

No studies on the effect of the drug on the ability to concentrate during driving or operating machinery have been conducted. No effect of COCs on the ability to concentrate during driving or operating machinery has been observed in individuals taking COCs.

Method of Administration and Dosage

For oral use.

Dosing

How to take Denovel® 30

Take 1 tablet daily for 21 consecutive days at approximately the same time each day, swallowing with a small amount of liquid if necessary, in the order indicated on the blister pack. The next pack should be started after the 7-day tablet-free interval, during which withdrawal bleeding usually occurs. Withdrawal bleeding typically begins on the 2nd–3rd day after the last tablet and may not have finished before starting the next pack.

Starting Denovel® 30

• If no hormonal contraceptives were used previously (previous 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 advisable to start Denovel® 30 the day after taking the last active (hormone-containing) tablet of the previous COC, or after the placebo tablets of the previous COC.

• Switching from a vaginal ring or transdermal patch

Start taking Denovel® 30 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 be due.

• Switching from a progestogen-only method ("mini-pill", injections, implants) or an intrauterine system containing progestogen

Denovel® 30 can be started at any time after stopping the "mini-pill" (or on the day of removal of an implant or intrauterine system; instead of the next injection, in case of injectable contraception). However, in all cases, it is recommended to use an additional non-hormonal (barrier) method of contraception during the first 7 days of taking the tablets.

• After first-trimester abortion

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

• After childbirth or second-trimester abortion

It is recommended to start taking the drug on days 21–28 after childbirth or second-trimester abortion. If starting later, an additional barrier method of contraception should be used during the first 7 days of tablet use. However, if sexual intercourse has already occurred, pregnancy should be ruled out before starting the COC, or wait for the onset of the first menstrual period.

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

What to do if a tablet is missed

If the delay in taking the 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 tablet exceeds 12 hours, contraceptive efficacy may be reduced. In such a case, two main principles should be followed:

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

Accordingly, 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, use a barrier method of contraception (e.g., condom) for the next 7 days. If sexual 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 have to 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 required. 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, a reduction in contraceptive protection can be avoided, provided tablets were taken correctly during the 7 days before the missed dose. Otherwise, follow the first option below and use additional contraceptive precautions 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. Start the next pack immediately after finishing the current one, without any break between packs. Withdrawal bleeding is unlikely to occur before finishing the second pack, although breakthrough bleeding or spotting may occur during tablet intake.
2. Alternatively, stop taking tablets from the current pack. In this case, the tablet-free interval should not exceed 7 days, including the days of missed tablets; then start taking tablets from the next pack.

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

Recommendations in case of gastrointestinal disturbances

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

Postponing withdrawal bleeding

To delay withdrawal bleeding, continue taking tablets from a new pack without a break. 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 the regular Denovel® 30 regimen after the usual 7-day tablet-free interval.

To shift the timing of withdrawal bleeding to another day of the week, shorten the tablet-free interval by the desired number of days. The shorter the interval, the more likely the absence of withdrawal bleeding and the higher the risk of breakthrough bleeding or spotting during intake of tablets from the next pack (similar to delaying withdrawal bleeding).

Additional information for special patient groups

Elderly patients

Do not use. Denovel® 30 is not indicated after menopause.

Patients with hepatic impairment

Denovel® 30 is contraindicated in women with severe liver disease (see section "Contraindications").

Patients with renal impairment

Denovel® 30 has not been specifically studied in patients with renal impairment. Available data do not indicate the need to modify the administration regimen in this patient group.

Children

The drug is indicated only after the onset of menstruation.

Overdose

Acute toxicity in case of combined overdose of dienogest and ethinylestradiol is very low. The likelihood of intoxication symptoms is low, even in children who accidentally ingest several tablets. Possible symptoms include nausea, vomiting, and withdrawal bleeding. Withdrawal bleeding may even occur in premenarcheal girls who accidentally take the medication.

Treatment.
Specific treatment is usually not required. Supportive therapy should be administered if necessary.

Adverse reactions

The data on the frequency of adverse reactions reported during clinical studies (N=4,942) with ethinylestradiol/dienogest used as an oral contraceptive are summarized in Table 3. Within each frequency group, adverse reactions are listed in order of decreasing severity. Frequency is defined as follows: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), and rare (≥ 1/10,000 to < 1/1,000). The list of additional adverse reactions identified only during post-marketing surveillance, for which frequency could not be estimated, is provided under the heading "Frequency unknown".

Table 3

System organ classes (MedDRA)	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			anaemia
Immune system disorders			hypersensitivity	exacerbation of symptoms of hereditary and acquired angioedema
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	ischaemic stroke, cerebral circulation disorder, dystonia
Eye disorders			dry eye, eye irritation, oscillopsia, visual disturbance	contact lens intolerance
Ear and labyrinth disorders			sudden hearing loss, tinnitus, vertigo, hearing impairment
Cardiac disorders			cardiovascular disorders, tachycardia1
Vascular disorders		hypertension, hypotension	VTE, ATE, PTE, thrombophlebitis, diastolic hypertension, orthostatic circulatory disturbances, hot flushes, varicose veins, venous disorders, venous pain
Respiratory, thoracic and mediastinal disorders			asthma, hyperventilation
Gastrointestinal disorders		abdominal pain2, nausea, vomiting, diarrhoea	gastritis, enteritis, dyspepsia
Skin and subcutaneous tissue disorders		acne, alopecia, rash3, pruritus4	allergic dermatitis, atopic dermatitis/ neurodermatitis, eczema, psoriasis, hyperhidrosis, chloasma, pigmentation disorders/ hyperpigmentation, seborrhoea, dandruff, hirsutism, skin disorders, skin reactions, cellulitis, spider angioma	urticaria, nodular erythema, multiform erythema
Musculoskeletal and connective tissue disorders			back pain, musculoskeletal discomfort, myalgia, limb pain
Reproductive system and breast disorders	breast tenderness5	abnormal withdrawal bleeding6, intermenstrual bleeding7, breast enlargement8, breast swelling, dysmenorrhoea, genital/vaginal discharge, ovarian cyst, pelvic pain	cervical dysplasia, adnexal cysts, adnexal pain, breast cyst, fibrocystic mastopathy, dyspareunia, galactorrhoea, menstrual cycle disturbance	breast discharge
General disorders and administration site conditions		increased fatigue9	chest pain, peripheral oedema, influenza-like illness, inflammation, pyrexia, irritability	fluid retention
Investigations		weight gain	increased blood triglycerides, hypercholesterolaemia, weight loss, weight changes
Congenital, familial and genetic disorders			manifestations of asymptomatic polymastia

1 including increased heart rate;

2 including upper and lower abdominal pain, abdominal discomfort/distension;

3 including maculopapular rashes;

4 including generalized pruritus;

5 including breast discomfort and breast tenderness;

6 including menorrhagia, hypomenorrhea, oligomenorrhea, and amenorrhea;

7 including vaginal bleeding and metrorrhagia;

8 including breast swelling and breast enlargement;

9 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 reported in women using combined oral contraceptives (COCs) and are discussed further in the section "Special warnings and precautions for use":

Tumors

• The incidence of breast cancer is very slightly increased among women taking COCs. Since breast cancer is rare in women under 40 years of age, the excess number of cases is small compared to the overall risk of developing breast cancer. A causal relationship with COC use has not been established.
• Liver tumors.
• Cervical cancer.

Other diseases/conditions

• Women with hypertriglyceridemia (increased risk of pancreatitis when taking COCs).
• Arterial hypertension.
• Development or worsening of conditions/diseases for which a definitive causal relationship with COC use has not been established: cholestatic jaundice and/or pruritus; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic uremic syndrome; chorea minor; herpes gestationis; hearing loss associated with otosclerosis.
• Hepatic dysfunction.
• Changes in glucose tolerance or effects on peripheral insulin resistance.
• Crohn’s disease, ulcerative colitis.
• Chloasma.

Types of interaction

Breakthrough bleeding and/or contraceptive failure may result from 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 is important. Healthcare professionals and patients are encouraged to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store out of the reach of children in the original packaging at a temperature not exceeding 30 °C.

Packaging. 21 tablets per blister; 1, 3, or 6 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. mibe GmbH Arzneimittel.

Manufacturer's address.

Muenchenstrasse 15, Breuna, Saxony-Anhalt, 06796, Germany.

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[1] On average, 5–7 cases per 10,000 woman-years based on the relative risk of using COCs containing levonorgestrel compared to non-users of COCs (approximately 2.3–3.6 cases).

[2] Based on meta-analysis data, the risk of VTE in women using COCs containing dienogest and ethinylestradiol is slightly increased compared to women using COCs containing levonorgestrel (risk ratio 1.57 with a 95% confidence interval of 1.07–2.30).