Angeletta (Tablets) Instructions for Use

Marketing Authorization Holder

Actavis Group PTC ehf. (Iceland)

Manufactured By

Laboratorios Leon Farma, S.A. (Spain)

ATC Code

G03AA15 (Chlormadinone and Ethinylestradiol)

Active Substances

Ethinylestradiol (Rec.INN registered by WHO)

Chlormadinone (Rec.INN registered by WHO)

Dosage Form

Angeletta

Film-coated tablets, 30 mcg + 2 mg: 21 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets pink in color, round, biconvex.

Excipients : lactose monohydrate – 75.27 mg, povidone K30 – 2.1 mg, corn starch – 5 mg, magnesium stearate – 0.6 mg.

Film coating composition opadry pink 02F240004 (hypromellose – 1.075 mg, titanium dioxide – 1.075 mg, talc – 0.41 mg, macrogol 6000 – 0.41 mg, iron oxide red dye (E172) – 0.03 mg) – 3 mg.

21 pcs. – blisters (1) – cardboard packs.

Clinical-Pharmacological Group

Monophasic oral contraceptive with antiandrogenic properties

Pharmacotherapeutic Group

Combined contraceptive agent (estrogen + gestagen)

Pharmacological Action

A combined contraceptive drug for oral administration. Long-term use of the drug leads to a decrease in the secretion of FSH and LH and, consequently, to the suppression of ovulation. Simultaneously, proliferation of the endometrium and its secretory transformation occur, preventing the implantation of a fertilized egg; the viscosity of the cervical mucus increases, which is accompanied by difficulty in the passage of sperm through the cervical canal and impairment of their motility.

Chlormadinone acetate is a gestagen with antiandrogenic properties, the action of which is based on the ability to displace androgens at specific receptors, excluding and weakening the effect of endogenous and exogenous androgens. The Pearl index is 0.291-0.698, depending on how carefully the woman adheres to the drug regimen. The daily dose of chlormadinone that provides complete suppression of ovulation is 1.7 mg. The required dose per cycle is 25 mg.

Ethinylestradiol is a synthetic estrogen. It significantly increases the production of sex hormone-binding globulin, thereby reducing the amount of free testosterone in the blood plasma. It interacts with specialized estrogen receptors in target organs (fallopian tubes, cervix, vagina, external genitalia, mammary gland ducts), causing endometrial proliferation. It inhibits the secretion of skin sweat glands.

In addition to reliable contraceptive action, the positive effect of the drug is manifested in the normalization of the menstrual cycle, reduction in the severity of premenstrual syndrome, frequency of iron deficiency anemia, dysmenorrhea, functional ovarian cysts, ectopic pregnancy, malignant neoplasms of the endometrium and ovaries, some forms of benign breast diseases and inflammatory diseases of the pelvic organs.

Pharmacokinetics

Chlormadinone acetate

After oral administration, it is rapidly and completely absorbed. C_max is reached after 1-2 hours. More than 95% of chlormadinone acetate is bound to human plasma proteins, predominantly to albumin.

Various reduction, oxidation, and conjugation processes with glucuronides and sulfates lead to the formation of numerous metabolites. The main metabolites in plasma are 3-alpha and 3-beta-hydroxy-chlormadinone acetate with T_1/2 not significantly different from non-metabolized chlormadinone acetate. The 3-hydroxy metabolites have antiandrogenic activity similar to that of chlormadinone acetate itself. In urine, metabolites are found mainly in the form of conjugates. After enzymatic cleavage, the main metabolite becomes 2-alpha-hydroxy-chlormadinone acetate; 3-hydroxy metabolites and dihydroxymetabolites are also formed.

The mean T_1/2 from plasma is approximately 34 hours (after a single dose) and about 36-39 hours (with multiple applications). After oral administration, chlormadinone acetate and its metabolites are excreted in approximately equal amounts by the kidneys and through the intestines.

Ethinylestradiol

It is rapidly and almost completely absorbed after oral administration, reaching C_max in plasma after 1.5 hours. Due to presystemic conjugation and metabolism in the liver, the absolute bioavailability is about 40% and is subject to strong individual variability (20-65%). Available literature data on ethinylestradiol plasma concentrations vary widely. About 98% of ethinylestradiol is bound to plasma proteins, almost exclusively to albumin.

Like natural estrogens, Ethinylestradiol is biotransformed via hydroxylation of the aromatic ring (mediated by the cytochrome P450 system). The main metabolite is 2-hydroxy-Ethinylestradiol, which is transformed into other metabolites and conjugates. Ethinylestradiol undergoes presystemic conjugation both in the small intestinal mucosa and in the liver. In urine, glucuronides are mainly found, and in bile and plasma, sulfates are found.

The mean T_1/2 from plasma is approximately 12-14 hours. Ethinylestradiol is excreted by the kidneys and through the intestines in a ratio of 2:3. Ethinylestradiol sulfate, excreted in bile after hydrolysis by intestinal bacteria, undergoes enterohepatic recirculation.

Indications

Oral contraception.

ICD codes

Dosage Regimen

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

Each tablet contains a fixed dose of 30 mcg ethinylestradiol and 2 mg chlormadinone acetate.

Follow a 21-day active cycle followed by a 7-day tablet-free interval.

Begin taking Angeletta on the first day of your menstrual cycle.

If starting later than day one of menstruation, use an additional barrier contraceptive method for the first 7 days of tablet-taking.

Take any missed tablet as soon as remembered, even if it means taking two tablets in one day.

If a single tablet is missed for more than 12 hours, contraceptive reliability may be reduced.

If vomiting or severe diarrhea occurs within 3-4 hours of taking a tablet, consider this a missed dose and follow the respective instructions.

During the 7-day tablet-free interval, withdrawal bleeding usually occurs.

Start the next pack on the 8th day after the last tablet, even if bleeding has not finished.

If no withdrawal bleeding occurs for two consecutive cycles, rule out pregnancy before continuing.

For postpartum use in non-breastfeeding women, initiation is no earlier than day 21 after delivery.

Following a first-trimester abortion, start immediately; after a second-trimester abortion, start after 21-28 days.

Adverse Reactions

When taking the combination Chlormadinone+Ethinylestradiol, the most common adverse reactions (more than 20% of cases) are breakthrough bleeding, vaginal spotting, headache, and breast discomfort. The frequency of acyclic bleeding usually decreases with increasing duration of use.

The frequency of adverse reactions is defined as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000).

Immune system disorders uncommon – hypersensitivity to the components of the drug, including skin allergic reactions; rare – urticaria.

Metabolism and nutrition disorders uncommon – changes in blood lipid composition, including hypertriglyceridemia.

Psychiatric disorders common – depressive state, nervousness, irritability; uncommon – decreased libido.

Nervous system disorders common – dizziness, migraine (and/or its exacerbation).

Eye disorders common – visual disturbances; rare – conjunctivitis, contact lens intolerance.

Ear and labyrinth disorders rare – sudden hearing loss, tinnitus.

Cardiac disorders rare – increased blood pressure, decreased blood pressure, cardiovascular collapse, varicose veins, arterial or venous thromboembolic complications.

Gastrointestinal disorders very common – nausea; common – vomiting; uncommon – abdominal pain, flatulence, diarrhea.

Skin and subcutaneous tissue disorders common – acne; uncommon – pigmentation disorders, chloasma, hair loss, dry skin, hyperhidrosis; rare – eczema, erythema, skin itching, exacerbation of psoriasis, hypertrichosis; very rare – erythema nodosum.

Musculoskeletal and connective tissue disorders common – feeling of heaviness; uncommon – back pain, muscle disorders.

Reproductive system and breast disorders very common – increased vaginal mucous discharge, painful menstrual-like bleeding, absence of menstrual-like bleeding; common – lower abdominal pain; uncommon – galactorrhea, breast fibroadenoma, vaginal candidiasis; rare – breast enlargement, vulvovaginitis, heavy menstrual-like bleeding, premenstrual syndrome.

General disorders and administration site conditions common – fatigue, edema, weight gain.

When using combined oral contraceptives, including those containing 0.03 mg ethinylestradiol and 2 mg chlormadinone acetate, the following undesirable effects have also been noted

• Increased risk of venous and arterial thromboembolism (e.g., venous thrombosis, pulmonary embolism, cerebrovascular disorders, myocardial infarction), the risk may be enhanced by additional factors;
• Increased risk of biliary tract disease;
• In rare cases, increased risk of benign liver tumors (and even more rarely – malignant liver tumors); isolated cases can lead to life-threatening intra-abdominal bleeding;
• Exacerbation of chronic inflammatory bowel diseases (Crohn’s disease, ulcerative colitis).

Contraindications

The use of the drug is contraindicated in the presence of the following conditions/risk factors/diseases

• Presence of thrombosis (venous and arterial) currently or in history (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular disorders);
• Presence of the first signs of thrombosis, thrombophlebitis or symptoms of thromboembolism (e.g., transient ischemic attacks, angina pectoris);
• Planned surgical intervention (at least 4 weeks before it) and the period of immobilization, for example, after trauma (including after application of plaster casts), and for at least 2 weeks after restoration of full mobility;
• Diabetes mellitus with vascular complications;
• Diabetes mellitus not adequately controlled;
• Uncontrolled arterial hypertension or significant increase in blood pressure (above 140/90 mm Hg);
• Hereditary or acquired predisposition to the development of venous or arterial thrombosis, including increased resistance to activated protein C (APC resistance); antithrombin III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
• Acute or chronic severe liver diseases (until liver function tests normalize);
• Generalized pruritus, cholestasis, especially during a previous pregnancy or history of taking sex hormones;
• Dubin-Johnson syndrome, Rotor syndrome, conditions/diseases accompanied by impaired bile outflow;
• Presence of liver tumors currently or in history;
• Severe epigastric pain, liver enlargement or symptoms of intra-abdominal bleeding;
• Newly diagnosed porphyria or its recurrence (all three forms, especially acquired porphyria);
• Presence of hormone-dependent malignant diseases, including in history (e.g., of the uterus or breasts), or suspicion of them;
• Severe lipid metabolism disorders;
• Pancreatitis (currently or in history) in combination with severe forms of hypertriglyceridemia;
• Newly occurring migraine attacks or frequent severe headaches;
• Migraine accompanied by focal neurological symptoms (associated migraine);
• Acute sensory disturbances, e.g., visual and hearing impairments;
• Motor disturbances (in particular, paresis);
• Increased frequency of epileptic seizures;
• Severe depression;
• Otosclerosis during previous pregnancies;
• Amenorrhea of unclear etiology;
• Endometrial hyperplasia;
• Vaginal bleeding of unclear etiology;
• Pregnancy or suspected pregnancy;
• Breastfeeding period;
• Smoking over the age of 35;
• Presence of pronounced or multiple risk factors for the development of arterial and venous thrombosis (increasing age, smoking, severe dyslipoproteinemia, obesity with BMI >30 kg/m², family history of venous or arterial insufficiency in first-line relatives, heart valve diseases, bacterial endocarditis, atrial fibrillation, surgical interventions on the lower extremities and pelvic area, neurosurgical operations, extensive trauma, air travel lasting more than 4 hours);
• Hypersensitivity to the components of the drug.

With caution

In the presence of the following conditions/risk factors/diseases currently or in history, the use of the drug requires careful medical supervision, assessment of potential risk and expected benefit: epilepsy; multiple sclerosis; convulsive syndrome (tetany); migraine without focal neurological symptoms; bronchial asthma; cardiac or renal failure; chorea minor; uncomplicated diabetes mellitus; mild to moderate liver diseases (with normal liver function tests); lipid metabolism disorders; dyslipoproteinemia; autoimmune diseases (including systemic lupus erythematosus); obesity (BMI <30 kg/m²); controlled arterial hypertension; endometriosis; varicose veins; superficial phlebitis of the lower extremities; blood clotting disorders; mastopathy; uterine fibroids; herpes gestationis; depression; chronic inflammatory bowel diseases (Crohn’s disease, ulcerative colitis).

Use in Pregnancy and Lactation

The use of the drug during pregnancy is contraindicated. Before starting the use of the drug, pregnancy must be excluded. If pregnancy occurs, the drug should be discontinued immediately. The data available to date do not contain information on the development of teratogenic or embryotoxic effects in women who accidentally took during pregnancy drugs containing estrogens and progesterones in the same combination as in the combined drug.

The use of the drug is contraindicated during breastfeeding, since the drug reduces the amount of milk produced and changes its composition. Small amounts of the hormones that make up the drug and/or their metabolites pass into breast milk and can affect the child’s body.

Use in Hepatic Impairment

The use of the drug is contraindicated in acute or chronic severe liver diseases (until liver function tests normalize), presence of liver tumors currently or in history.

With caution: mild to moderate liver diseases (with normal liver function tests).

Use in Renal Impairment

With caution: renal failure.

Special Precautions

Smoking increases the risk of developing serious adverse reactions from the cardiovascular system when using combined oral contraceptives. The risk increases with age and depends on the number of cigarettes smoked. The risk is more pronounced in women over 35 years of age. Women who smoke and are over 35 years of age should use other methods of contraception.

When using combined oral contraceptives, the risk of developing serious diseases increases: myocardial infarction, thrombosis/thromboembolism, cerebrovascular disorders and liver neoplasms. Other risk factors, such as arterial hypertension, hyperlipidemia, obesity and diabetes mellitus, clearly increase the risk of morbidity and mortality. If one of the above diseases/risk factors is present, it is necessary to weigh the potential risk and expected benefit of using the drug, and also discuss this with the woman before she starts taking this drug. If these diseases or risk factors occur or progress during the use of the drug, the woman should consult her doctor. The doctor must decide whether to continue or stop treatment.

Thromboembolism and other vascular diseases

It has been noted that there is a relationship between the use of combined oral contraceptives and an increased risk of venous and arterial thromboembolic diseases, for example, myocardial infarction, cerebrovascular disorders, deep vein thrombosis or pulmonary embolism. These complications are rare.

In very rare cases, thrombosis of vessels of rare localization (liver, mesentery, kidney, brain, retina) has been reported with the use of oral contraceptives. The use of combined oral contraceptives leads to an increased risk of venous thromboembolism (VTE). The risk of VTE is highest during the first year of use. The degree of this risk is less than during pregnancy, when the frequency of VTE is 60 cases per 100,000 pregnancies. VTE leads to death in 1-2% of cases.

The risk of developing venous thromboembolic complications when taking combined oral contraceptives increases: with age; in the presence of thromboembolism in relatives (venous thromboembolism in siblings or parents at a relatively young age; if a hereditary predisposition is suspected, it is recommended to refer the woman for a specialist consultation before prescribing the drug); with prolonged immobilization; with obesity (BMI >30 kg/m²); with extensive surgical interventions; with any operations on the lower extremities and pelvic area; with neurosurgical operations; with extensive trauma; with air travel lasting more than 4 hours.

It is recommended to stop taking the drug for the entire period of immobilization and for at least 2 weeks after the patient’s full mobility is restored.

The risk of developing arterial thromboembolic complications when taking combined oral contraceptives increases: with age; in smokers; with dyslipoproteinemia; obesity (BMI >30 kg/m²); arterial hypertension; heart defects; atrial fibrillation; presence of thromboembolism in relatives (arterial thromboembolism in siblings or parents at a relatively young age). If a hereditary predisposition is suspected, it is recommended to refer the woman for a specialist consultation before prescribing the drug.

The risk of developing thromboembolic complications increases in the presence of a pronounced or a combination of several risk factors.

Other diseases affecting blood circulation include: diabetes mellitus, systemic lupus erythematosus, hemolytic-uremic syndrome, chronic inflammatory bowel diseases (Crohn’s disease and ulcerative colitis), sickle cell anemia. When assessing the risk/benefit, it should be remembered that adequate treatment of the aforementioned conditions can reduce the risk of thrombosis. The increased risk of thromboembolic complications in the postpartum period must be taken into account.

There is no consensus on whether a relationship exists between superficial vein thrombophlebitis and/or varicose veins and the etiology of venous thromboembolism. If venous or arterial thrombosis develops, the following symptoms may occur: pain in the lower limbs and/or swelling; sudden severe chest pain, with or without radiation to the left arm; sudden shortness of breath, coughing for no apparent reason; sudden severe prolonged headache; partial or complete loss of vision; diplopia/speech disorders or aphasia; dizziness, collapse, in some cases accompanied by a focal epileptic seizure; sudden weakness or dysesthesia (sensory distortion) on one side or in one part of the body; motor disorders; acute abdominal pain.

Women taking the drug should be informed that if symptoms resembling thrombosis appear, they must consult their attending physician. The drug should be discontinued if thrombosis is suspected or diagnosed.

An increase in the frequency or severity of migraine attacks during drug use (which may be a precursor to or a symptom of cerebrovascular disease) is an indication for immediate drug withdrawal.

Tumors

The use of combined oral contraceptives has been noted as a risk factor for the development of cervical cancer in women infected with the human papillomavirus. However, the extent to which other concomitant factors (such as the number of sexual partners or the use of mechanical contraceptives) influence the results of this observation remains controversial. There is evidence that the relative risk (RR=1.24) of developing breast cancer is slightly higher in women who use combined oral contraceptives. Within 10 years after discontinuation of combined oral contraceptives, the risk level gradually decreases and returns to the age-specific level. Since breast cancer is rare in women under 40 years of age, the difference between the degree of breast cancer risk in current and recent users of combined oral contraceptives and the overall risk of developing the disease is small.

There have been rare reports of the development of benign, and even rarer cases of malignant liver tumors during the use of combined oral contraceptives. In some cases, these tumors have caused life-threatening intra-abdominal bleeding. If severe abdominal pain that does not resolve on its own, hepatomegaly, or signs of intra-abdominal bleeding occur, the possibility of a liver tumor should be considered, and the drug should be discontinued.

Other Diseases

Many women taking oral contraceptives experience a slight increase in blood pressure; however, clinically significant increases are rare. The relationship between the use of oral contraceptives and the clinical manifestation of arterial hypertension has not been confirmed to date. If a clinically significant increase in blood pressure occurs during drug use, the drug should be discontinued and arterial hypertension should be treated. Once blood pressure levels normalize after antihypertensive therapy, the drug can be resumed.

In women with a history of herpes gestationis, a relapse of the disease is possible while taking the drug. In women with a personal or family history of hypertriglyceridemia, the risk of pancreatitis increases while taking the drug. In cases of acute or chronic liver dysfunction, it may be necessary to discontinue the drug until liver function tests normalize. If cholestatic jaundice recurs, which was first diagnosed during pregnancy or while taking sex hormones, the drug should be discontinued.

The use of combined oral contraceptives may affect peripheral insulin resistance or glucose tolerance. Therefore, patients with diabetes mellitus who are taking oral contraceptives should be carefully monitored.

In rare cases, chloasma may appear, especially in women with a history of chloasma during pregnancy. Women predisposed to chloasma should avoid sun exposure and UV radiation while taking the drug.

Medical Examination

Before prescribing the drug, a medical examination must be conducted and complete health data of the woman and her relatives must be collected to identify contraindications and risk factors. A medical examination should be performed every 6 months during drug use. Regular medical examination is also necessary because conditions that are contraindications (e.g., transient ischemic attacks) or risk factors (e.g., venous or arterial thrombosis) may first appear during drug use.

The medical examination should include blood pressure measurement, examination of the breasts, abdominal and pelvic organs, including cytological examination of the cervical epithelium and appropriate laboratory tests.

The woman should be warned that the use of oral contraceptives does not protect her from HIV infection (AIDS) or other sexually transmitted diseases.

Reduced Efficacy

Missing a tablet, vomiting and diarrhea, prolonged concurrent use of certain medications or, in very rare cases, metabolic disorders can reduce contraceptive efficacy.

Effect on the Menstrual Cycle

The use of all oral contraceptives can lead to vaginal bleeding (breakthrough bleeding and spotting), especially during the first cycles of drug use. Therefore, a medical examination for irregular cycles should be performed only after an adaptation period, which usually lasts for 3 cycles. If breakthrough bleeding persists or first appears during drug use, although the cycle was previously regular, an examination should be performed to rule out pregnancy or organic diseases. After excluding pregnancy or an organic disease, the drug can be continued or switched to another drug.

Acyclic bleeding may be a sign of reduced contraceptive efficacy.

Absence of Menstrual-like Bleeding

Typically, withdrawal bleeding occurs after 21 days of taking the drug. Sometimes, especially during the first few months of drug use, “withdrawal” bleeding may be absent. However, this is not evidence of insufficient contraceptive effect. If bleeding does not occur after taking the drug for one cycle, provided that no film-coated tablet was missed, the period after completing the drug intake did not exceed 7 days, no other medications were taken concurrently, and there was no vomiting or diarrhea, the drug can be continued. If the instructions for drug use were not followed before the first absence of withdrawal bleeding, or withdrawal bleeding was absent for two consecutive cycles, pregnancy must be ruled out before deciding whether to continue taking the drug.

Concurrently with taking the drug, one should not take herbal medicines containing St. John’s wort (Hypericum perforatum).

Laboratory Parameters

During drug use, changes in some laboratory parameters may occur, including the functional activity of the liver, adrenal glands, and thyroid gland, the concentration of binding proteins in plasma (e.g., sex hormone-binding globulin, lipoproteins), parameters of carbohydrate metabolism, coagulation, and fibrinolysis. The nature and degree of changes are partly determined by the nature and dose of the hormones taken.

Effect on the Ability to Drive Vehicles and Machinery

Hormonal contraceptive drugs do not affect the ability to drive vehicles and machinery.

Drug Interactions

Interaction of ethinylestradiol, the estrogenic component of the drug, with other medicinal products can cause an increase or decrease in the plasma concentration of ethinylestradiol. If long-term treatment with these drugs is necessary, a switch to non-hormonal methods of contraception should be made. A decrease in the plasma concentration of ethinylestradiol can lead to an increase in breakthrough bleeding episodes, cycle irregularities, and a decrease in the contraceptive efficacy of the drug. An increase in the plasma concentration of ethinylestradiol can increase the frequency and severity of side effects.

Medicinal Products/Active Substances that Reduce the Plasma Concentration of Ethinylestradiol

• All drugs that increase gastrointestinal motility (e.g., metoclopramide) or impair absorption (e.g., activated charcoal);
• Active substances that induce hepatic microsomal enzymes, such as rifampicin, rifabutin, barbiturates, anticonvulsants (e.g., carbamazepine, oxcarbazepine, phenytoin, topiramate, felbamate), phenylbutazone, griseofulvin, barbexaclone, primidone, modafinil, some protease inhibitors (e.g., ritonavir) and preparations of St. John’s wort;
• Some antibiotics (e.g., ampicillin, tetracycline, rifampicin) – due to reduced enterohepatic recirculation of estrogens.

When such drugs/active substances are used concurrently with the drug, additional barrier methods of contraception must be used, both during treatment and for 7 days after it.

Medicinal Products/Active Substances that Increase the Plasma Concentration of Ethinylestradiol

• Active substances that inhibit the sulfation of ethinylestradiol in the intestinal wall, for example, ascorbic acid or paracetamol;
• Atorvastatin (increases the AUC of ethinylestradiol by 20%);
• Active substances that inhibit the activity of hepatic microsomal enzymes, such as antifungal agents derived from imidazole (e.g., fluconazole), indinavir, or troleandomycin.

Effect of Ethinylestradiol on the Metabolism of Other Substances

Ethinylestradiol inhibits the activity of hepatic microsomal enzymes and, accordingly, increases the plasma concentration of active substances such as diazepam (and other benzodiazepines metabolized via hydroxylation), cyclosporine, theophylline, and prednisolone.

Ethinylestradiol induces glucuronidation in the liver and, accordingly, reduces the plasma concentration of, for example, clofibrate, paracetamol, morphine, and lorazepam.

The requirement for insulin and oral hypoglycemic drugs may change due to the drug’s effect on glucose tolerance.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°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.