Diane-35^® (Tablets) Instructions for Use

Marketing Authorization Holder

Bayer, AG (Germany)

Manufactured By

Bayer Weimar, GmbH & Co. KG (Germany)

ATC Code

G03HB01 (Cyproterone and estrogens)

Active Substances

Cyproterone (Rec.INN registered by WHO)

Ethinylestradiol (Rec.INN registered by WHO)

Dosage Form

Diane-35®

Film-coated tablets 2 mg+0.035 mg: 21 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light yellow in color, round, biconvex.

Excipients: lactose monohydrate, corn starch, povidone 25, talc (magnesium hydrosilicate), magnesium stearate.

Shell composition sucrose, povidone 90, macrogol 6000, calcium carbonate, talc (magnesium hydrosilicate), titanium dioxide, glycerol 85%, glycol montan wax, yellow iron (II) oxide dye.

21 pcs. – blisters (1) – cardboard packs with first opening control.

Clinical-Pharmacological Group

Monophasic oral contraceptive with antiandrogenic properties

Pharmacotherapeutic Group

Combined contraceptive agent (estrogen + antiandrogen)

Pharmacological Action

A combined low-dose monophasic contraceptive with antiandrogenic activity. The mechanism of action is due to its constituent antiandrogenic agent of steroid structure – cyproterone acetate and the oral estrogen – ethinylestradiol. It blocks androgen receptors and inhibits the secretion of gonadotropic hormones by the pituitary gland.

Cyproterone has the ability to competitively bind to receptors of natural androgens (including testosterone, dihydroepiandrosterone, androstenedione), produced in small amounts in the female body, mainly in the adrenal glands, ovaries, and skin. By blocking androgen receptors in target organs, it reduces the phenomena of androgenization in women (by disrupting processes mediated by hormone-receptor complexes at the level of basic intracellular mechanisms). Along with antiandrogenic properties, it has progestogenic activity, mimicking the properties of the corpus luteum hormone. It inhibits the secretion of gonadotropic hormones by the pituitary gland and inhibits ovulation, which determines its contraceptive effect.

Ethinylestradiol enhances the central and peripheral effects of cyproterone on ovulation, maintains high viscosity of cervical mucus, which impedes the penetration of sperm into the uterine cavity and contributes to ensuring reliable contraceptive effect.

Pharmacokinetics

Cyproterone is completely absorbed after oral administration. C_max in blood serum is reached after 1.6 h when taken in combination with ethinylestradiol and is 15 ng/ml. Bioavailability is 88%. It is almost completely bound to plasma albumins. During the course of treatment, accumulation is observed: serum concentration increases from 15 ng/ml on the 1st day of treatment to 21 ng/ml at the end of the 1st cycle and to 24 ng/ml at the end of the 3rd cycle of treatment. AUC increases by 2.2 times (end of the 1st cycle) and by 2.4 times (end of the 3rd cycle). C_ss is achieved approximately after 16 days from the start of treatment. It is metabolized in the liver through various reactions, including hydroxylation and conjugation. The main metabolite is 15-hydroxycyproterone. T_1/2 from plasma is biphasic, T_1/2 is 0.8 h and 2.3 days for the first and second phase, respectively. Total plasma clearance is 3.6 ml/min/kg. The main part of the administered dose is excreted by the kidneys as metabolites, the remaining part is excreted with bile unchanged. T_1/2 is 1.9 days.

After oral administration, Ethinylestradiol is rapidly and completely absorbed. C_max in blood serum is reached after 1.7 h and is 80 pg/ml. It is almost completely bound to plasma proteins. During absorption and the “first pass” through the liver, it is metabolized, which leads to a decrease in bioavailability. The apparent V_d is 5 l/kg. C_ss is achieved after 3-4 days from the start of treatment. T_1/2 from plasma is biphasic, T_1/2 is 1-2 h and 20 h for the first and second phase, respectively. Plasma clearance is 5 ml/min/kg. It is excreted as metabolites through the intestines and kidneys in a ratio of 4:6, T_1/2 is about 1 day.

Indications

Contraception in women with signs of androgenization; treatment of androgen-dependent diseases/conditions in women (“vulgar” acne (acne papulopustulosa, acne nodulocystica); seborrhea; androgenic alopecia; hirsutism).

ICD codes

Dosage Regimen

Take one tablet orally once daily, at approximately the same time each day.

Follow the blister pack sequence strictly. Take tablets for 21 consecutive days, followed by a 7-day tablet-free interval.

Begin treatment on the first day of your menstrual cycle. Start a new pack after the 7-day break, even if menstrual bleeding has not ended.

If switching from another combined hormonal contraceptive, start Diane-35 the day after the last active tablet of the previous product.

After a miscarriage or abortion in the second trimester, start immediately. After a first-trimester abortion or childbirth, start between day 21 and 28 postpartum; if started later, use a barrier method for the first 7 days.

If a tablet is taken 12 hours late, take it immediately and continue the schedule as usual; contraceptive protection remains.

If a tablet is taken more than 12 hours late, contraceptive reliability may be reduced. Take the missed tablet immediately, even if it means taking two tablets on the same day.

Continue taking the remaining tablets at the usual time. Use a non-hormonal barrier method of contraception for the next 7 days.

If these 7 days run beyond the last tablet in the pack, start the next pack immediately without a break. There will be no withdrawal bleed, but breakthrough bleeding may occur.

If vomiting or severe diarrhea occurs within 3-4 hours of taking a tablet, handle it as a missed tablet. Use additional barrier contraception until the next cycle starts normally.

To delay a period, finish the current pack and start the next pack the next day without a break. Withdrawal bleeding will occur after the second pack is finished.

Discontinue use immediately if pregnancy is confirmed, or if symptoms of thrombosis, severe liver disease, or significant hypertension occur.

Adverse Reactions

Definition of frequency of adverse reactions: common (>1/100 and <1/10); uncommon (>1/1000 and <1/100); rare (>1/10,000 and <1/1000).

From the nervous system common – headache, depression, mood changes; uncommon – migraine, decreased libido; rare – increased libido.

From the digestive system common – nausea, abdominal pain; uncommon – vomiting, diarrhea.

From the reproductive system and breast common – breast pain, breast engorgement; uncommon – breast hypertrophy; rare – intermenstrual bleeding, oligomenorrhea.

Other common – weight gain; uncommon – fluid retention in the body, rash, urticaria; rare – allergic reactions, erythema nodosum, erythema multiforme, weight loss, worsening of contact lens tolerance, with long-term use – chloasma.

All women taking combined oral contraceptives (COCs) are at increased risk of thrombosis and thromboembolism, and some increase in the risk of occurrence and worsening of other diseases. When taking COCs, irregular (acyclic) vaginal bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use.

Contraindications

Thrombosis (venous and arterial) and thromboembolism currently or in history (including deep vein thrombosis, pulmonary embolism), coronary artery disease, stroke; conditions preceding thrombosis (including transient ischemic attacks, angina) currently or in history; complicated heart valve lesions (pulmonary hypertension, atrial fibrillation, history of subacute bacterial endocarditis); uncontrolled arterial hypertension (systolic BP above 160 mm Hg or diastolic BP above 100 mm Hg); major surgery with prolonged immobilization; diabetes mellitus with vascular complications; multiple or pronounced risk factors for venous or arterial thrombosis, including cerebrovascular or coronary artery disease, arterial hypertension, older age; hepatic failure and severe liver diseases (until liver tests normalize); active viral hepatitis, decompensated liver cirrhosis; idiopathic jaundice or pruritus during a previous pregnancy; congenital hyperbilirubinemias (Gilbert, Dubin-Johnson and Rotor syndromes); liver tumors (benign or malignant) currently or in history; migraine with focal neurological symptoms currently or in history; pancreatitis with severe hypertriglyceridemia currently or in history; identified hormone-dependent malignant diseases (including breast cancer and endometrial cancer) or suspicion of them; vaginal bleeding of unknown origin; sickle cell anemia; otosclerosis worsened during pregnancy; herpes during pregnancy in history; smoking over the age of 35; pregnancy; lactation period; hypersensitivity to any component of the combination.

With caution

The potential risk and expected benefit of using COCs should be carefully weighed in each individual case in the presence of the diseases/conditions and risk factors listed below.

Risk factors for thrombosis: smoking, obesity, dyslipoproteinemia, arterial hypertension, migraine, heart valve defects, prolonged immobilization, major surgical interventions, extensive trauma, hereditary predisposition to thrombosis (thrombosis, blood clotting disorders, myocardial infarction or cerebrovascular accident at a young age in any of the immediate relatives).

Diseases in which peripheral circulation disorders may be noted: diabetes mellitus (or predisposition, for example, unexplained glucosuria), systemic lupus erythematosus (SLE), impaired renal function, hemolytic-uremic syndrome, Crohn’s disease and ulcerative colitis (UC), varicose veins, superficial phlebitis.

Hypertriglyceridemia; liver diseases; family history of breast cancer or personal history of benign breast tumor; diagnosed depression in history; uterine fibroids; cholelithiasis; contact lens intolerance; diseases that first appeared or worsened during pregnancy or against the background of previous use of sex hormones (for example, jaundice and/or pruritus associated with cholestasis, cholelithiasis, porphyria, Sydenham’s chorea, chloasma).

Use in Pregnancy and Lactation

Use is contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

Use is contraindicated in hepatic failure and severe liver diseases (until liver tests normalize), active viral hepatitis, decompensated liver cirrhosis, liver tumors (benign or malignant) currently or in history.

Use with caution in liver diseases.

Use in Renal Impairment

The drug should be used with caution in impaired renal function.

Special Precautions

Before starting or resuming the use of drugs containing this combination, a woman must undergo a thorough general medical (including measurement of BP, heart rate, determination of BMI) and gynecological examination, including examination of the mammary glands and cytological examination of a cervical smear (Pap test), and exclude pregnancy. The scope of additional studies and the frequency of follow-up examinations is determined individually. Usually, follow-up examinations should be carried out at least 2 times a year.

The woman should be warned that this combination does not protect against HIV infection and other sexually transmitted diseases.

There is evidence of an increased incidence of venous and arterial thrombosis and thromboembolism (such as deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) when using COCs. These diseases are rare. The risk of developing venous thromboembolism is maximum in the first year of taking such drugs. The risk of developing thrombosis (venous and/or arterial) and thromboembolism increases: with age; in smokers (with an increase in the number of cigarettes or with increasing age, the risk further increases, especially in women over 35 years old) in the presence of a burdened family history (for example, venous or arterial thromboembolism ever in close relatives or parents at a relatively young age). In case of hereditary predisposition, the woman should be referred to an appropriate specialist to decide on the possibility of using COCs; with obesity (BMI > 30 kg/m²), dyslipoproteinemia, arterial hypertension, migraine, heart valve diseases, atrial fibrillation, prolonged immobilization, major surgery, any operation on the lower extremities or extensive trauma. In these situations, it is necessary to stop using COCs (in the case of planned surgery, at least 4 weeks before it) and not resume taking it within 2 weeks after the end of immobilization.

The question of the possible role of varicose veins and superficial thrombophlebitis in the development of venous thromboembolism remains controversial.

The increased risk of thromboembolism in the postpartum period should be taken into account.

Peripheral circulation disorders can also be observed in diabetes mellitus, SLE, tetany, hemolytic-uremic syndrome, chronic inflammatory bowel diseases (Crohn’s disease or UC) and sickle cell anemia.

An increase in the frequency and severity of migraine during the use of COCs (which may precede cerebrovascular disorders) may be a reason for immediate discontinuation of these drugs.

An important risk factor for cervical cancer is the persistence of papillomavirus. The results of some epidemiological studies indicate an additional increase in this risk with long-term use of COCs, however, this statement remains controversial, since it is not definitively established to what extent the study results take into account concomitant risk factors, for example, cervical screening and sexual behavior, including less frequent use of barrier methods of contraception.

The relationship between the use of COCs and breast cancer has not been proven. There is a slightly increased relative risk of developing breast cancer diagnosed in women currently taking COCs. The increased risk gradually disappears within 10 years after stopping the use of these drugs. The observed increase in risk may be a consequence of careful monitoring and earlier diagnosis of breast cancer in women using COCs. In women who have ever used COCs, earlier stages of breast cancer are detected and it is clinically less pronounced than in women who have never used COCs.

In isolated cases, against the background of the use of COCs, the development of benign, and in extremely rare cases, malignant liver tumors was observed, which in some cases led to life-threatening intra-abdominal bleeding. In the event of severe abdominal pain, liver enlargement or signs of intra-abdominal bleeding, the possibility of a liver tumor should be considered in the differential diagnosis in patients taking COCs.

In women with hypertriglyceridemia (or a family history of this condition), an increased risk of developing pancreatitis is possible during the use of COCs.

Although a slight increase in BP has been described in many women taking COCs, a clinically significant increase in BP was rarely noted. However, if during the use of COCs a persistent, clinically significant increase in BP develops, these drugs should be discontinued and treatment for arterial hypertension should be started. Taking COCs can be continued if normal BP values are achieved with antihypertensive therapy.

The following conditions have been reported to develop or worsen both during pregnancy and when taking COCs, but their connection with taking COCs has not been proven: jaundice and/or pruritus associated with cholestasis; formation of gallstones; porphyria; SLE; hemolytic-uremic syndrome; Sydenham’s chorea; herpes of pregnancy; hearing loss associated with otosclerosis. Cases of Crohn’s disease and UC against the background of COC use have also been described.

In women with hereditary forms of angioedema, exogenous estrogens may cause or worsen the symptoms of angioedema.

Acute or chronic liver dysfunction may require discontinuation of COCs until liver function tests return to normal. Recurrent cholestatic jaundice, which develops for the first time during pregnancy or previous use of sex hormones, requires discontinuation of COCs.

Although COCs can affect insulin resistance and glucose tolerance, there is no need to change the therapeutic regimen in patients with diabetes mellitus using low-dose COCs (<0.05 mg ethinylestradiol). Nevertheless, women with diabetes mellitus should be carefully monitored during the use of COCs.

Chloasma may sometimes develop, especially in women with a history of chloasma of pregnancy. Women prone to chloasma during the use of COCs should avoid prolonged exposure to the sun and ultraviolet radiation.

Treatment (contraception) must be stopped immediately if pregnancy occurs, if migraine-like headaches develop (if they were not present before), if early signs of phlebitis or phlebothrombosis appear (unusual pain or swelling of the veins in the lower extremities), if jaundice, visual disturbances, cerebrovascular disorders, stabbing pains of unknown etiology when breathing or coughing, pain and a feeling of tightness in the chest, if blood pressure increases.

Intake is also stopped 3 months before the planned pregnancy, 6 weeks before the planned surgical intervention and during prolonged immobilization.

Taking COCs can affect the results of some laboratory tests, including indicators of liver, kidney, thyroid, adrenal function, the content of transport proteins in plasma, indicators of carbohydrate metabolism, parameters of coagulation and fibrinolysis.

Changes in the results of skin allergy tests, a decrease in the concentration of LH and FSH are possible.

Since the contraceptive effect is fully manifested by the 14th day from the start of administration, it is recommended to additionally use non-hormonal (barrier) methods of contraception during the first 2 weeks.

Prescription after childbirth is recommended no earlier than the first normal menstruation after childbirth.

In cases of acyclic bloody discharge during the first 3 weeks of hormonal contraception, it is possible to continue taking the drug, as a rule, the bloody discharge stops on its own. If there is no bleeding during the 7-day interval between taking the drug, taking the tablets should be stopped until pregnancy is excluded.

Against the background of the use of COCs, irregular (acyclic) bloody discharge/vaginal bleeding (spotting or breakthrough bleeding) may be noted, especially during the first months of use. Therefore, the assessment of any irregular bleeding should be carried out after an adaptation period of approximately three cycles.

If irregular bleeding recurs or develops after previous regular cycles, a thorough examination should be performed to rule out malignant neoplasms or pregnancy.

Drug Interactions

The effect on hepatic metabolism of drugs that induce microsomal liver enzymes may lead to an increase in the clearance of sex hormones, which in turn can lead to breakthrough bleeding or reduced contraceptive reliability. Such medicinal products include: phenytoin, barbiturates, primidone, carbamazepine, rifampicin, rifabutin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, and preparations containing St. John’s wort.

HIV protease inhibitors (e.g., ritonavir) and non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine) and their combinations may also potentially affect hepatic metabolism.

While using drugs that affect microsomal liver enzymes and for 28 days after their discontinuation, an additional barrier method of contraception should be used.

Some antibiotics (e.g., penicillins and tetracyclines) may reduce the enterohepatic circulation of estrogens, thereby lowering the concentration of ethinylestradiol. While using antibiotics (such as penicillins and tetracyclines) and for 7 days after their discontinuation, an additional barrier method of contraception should be used.

Combined oral contraceptives (COCs) can affect the metabolism of other drugs, leading to an increase (e.g., cyclosporine) or decrease (e.g., lamotrigine) in their plasma and tissue concentrations. An adjustment of the drug dosage regimen may be required.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.