Norcolut^® (Tablets) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

Contact Information

GEDEON RICHTER JSC (Hungary)

ATC Code

G03DC02 (Norethisterone)

Active Substance

Norethisterone (Rec.INN registered by WHO)

Dosage Form

Norcolut®

Tablets 5 mg: 20 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, round, flat, with a beveled edge, marked “NORCOLUT•” on one side and “+” on the other.

Excipients: potato starch, magnesium stearate, colloidal silicon dioxide, gelatin, talc, corn starch, lactose monohydrate.

10 pcs. – blisters (2) – cardboard packs.

Clinical-Pharmacological Group

Gestagen

Pharmacotherapeutic Group

Progestogen

Pharmacological Action

Norethisterone is a progestogen. It promotes the transformation of the uterine mucosa from the proliferative to the secretory phase. Norethisterone inhibits the secretion of gonadotropic hormone by the pituitary gland, preventing follicle maturation and ovulation.

Pharmacokinetics

Absorption

Well absorbed from the gastrointestinal tract. Due to intensive primary metabolism in the liver and intestinal wall, bioavailability is 50-77%. Norethisterone is characterized by a pronounced first-pass effect through the liver.

Distribution

After 0.5-4 hours of taking norethisterone at a dose of 0.5 mg, 1 mg, or 3 mg, C_max in blood plasma is 2-5 ng/ml, 5-10 ng/ml, or 30 ng/ml, respectively. When used in combination with ethinylestradiol, plasma concentrations of norethisterone may be higher and, in the case of multiple doses, increase until steady state is reached. This is mainly due to the binding of norethisterone to SHBG and the slowing of its metabolism.

Metabolism

The most important metabolites of norethisterone are individual isomers of 5-alpha-dihydronorethisterone and tetrahydronorethisterone, which are excreted mainly as conjugates with glucuronic acid. Conjugation reactions of norethisterone and some of its metabolites occur at the 17-beta-hydroxy group position.

Excretion

The decrease in plasma concentration of norethisterone occurs in two phases. T_1/2 in the first phase is 2.5 hours, in the terminal phase – 8 hours. 80% of the metabolites formed in the liver are excreted by the kidneys.

Indications

• Premenstrual syndrome;
• Mastodynia;
• Menstrual cycle disorders (including disorders with a shortened secretory phase);
• Dysfunctional uterine bleeding;
• Glandular-cystic hyperplasia of the endometrium;
• Endometriosis;
• Adenomyosis.

ICD codes

Dosage Regimen

The drug is taken orally with a small amount of water.

Premenstrual syndrome, mastodynia, menstrual cycle disorders 5-10 mg/day (1-2 tablets) from day 16 to day 25 of the menstrual cycle.

For other menstrual cycle disorders (if the absence of any gynecological diseases is confirmed by histological examination) 5-10 mg/day (1-2 tablets) for 6-12 days. To prevent recurrence 5-10 mg/day (1-2 tablets) from day 16 to day 25 of the menstrual cycle.

Endometriosis, adenomyosis 5 mg/day (1 tablet) from day 5 to day 25 of the menstrual cycle for 6 months. With long-term use, therapy should be started with a dose of 2.5 mg/day (1/2 tablet) on day 5 of the menstrual cycle; to prevent intermenstrual bleeding, the dose must be increased by 1/2 tablet every 2-3 weeks over 4-6 months.

Use of Norcolut^® in elderly patients is not indicated.

The efficacy and safety of norethisterone in patients with renal impairment have not been studied.

The efficacy and safety of norethisterone in patients with hepatic impairment have not been studied. However, as with all sex hormones, the use of norethisterone in patients with severe hepatic impairment is contraindicated.

If the taken dose was exceeded, the attending physician should be informed.

Before discontinuing this drug, the patient should consult with the attending physician.

Adverse Reactions

Adverse reactions occur more frequently in the first months of norethisterone use and decrease with increasing duration of therapy.

Definition of adverse reaction frequency: very common (>1/10), common (<1/10), uncommon (<1/100), rare (<1/1000), very rare (<1/10000), unknown (frequency cannot be estimated from the available data).

Reproductive system and breast disorders very common – uterine/vaginal bleeding

Metabolism and nutrition disorders common – fluid retention; rare – impaired glucose tolerance.

Nervous system disorders common – headache; uncommon – migraine

Psychiatric disorders uncommon – depressed mood.

Cardiac disorders rare – increased blood pressure; possibly – increased risk of arterial and venous thrombotic and thromboembolic complications, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis, and pulmonary embolism.

Gastrointestinal disorders common – nausea; uncommon – vomiting; possibly – liver tumors.

Hepatobiliary disorders rare – impaired liver function, impaired bile secretion, cholestatic jaundice, cholestasis; possibly – liver tumors.

Skin and subcutaneous tissue disorders rare – rash, skin itching; unknown – acne, chloasma (sometimes persistent after discontinuation), melanoderma (skin pigmentation spots due to excessive pigment deposition, most often on the skin of the face, hands, décolleté).

Allergic reactions in rare cases – urticaria, rapidly developing tissue edema, severe cardiac and respiratory system disorders, such as a sharp decrease in blood pressure, dizziness, feeling unwell, shortness of breath.

Eye and ear disorders very rare – visual impairment; unknown (frequency cannot be estimated); unknown – contact lens intolerance, hearing impairment

General disorders and administration site conditions very rare – shortness of breath; unknown – feeling of tightness in the chest.

If adverse reactions listed in the instructions are noted, or they worsen, or any other adverse reactions not listed above develop, the patient must inform the doctor.

Contraindications

• Hypersensitivity to norethisterone or any of the excipients of the drug;
• Hormone-dependent breast cancer (current or history);
• Hormone-dependent cancer of the genital organs (current or history);
• Presence of venous thromboembolism currently or in history, including deep vein thrombosis (DVT), pulmonary embolism (PE), thrombosis of other organs;
• Established disease accompanied by increased thrombosis, for example, protein C deficiency, protein S deficiency, antithrombin III deficiency, factor V Leiden mutation, or antiphospholipid antibodies;
• Upcoming surgery or upcoming prolonged immobilization;
• History of myocardial infarction or stroke;
• Angina pectoris, transient ischemic attack – current or history;
• Migraine with “aura”;
• In the presence of any of the following diseases that may increase the risk of arterial thrombosis:
  • Severe diabetes mellitus with vascular involvement;
  • Severe arterial hypertension;
  • Severe hypercholesterolemia and hypertriglyceridemia;
  • Hyperhomocysteinemia;
• Hypogonadal amenorrhea;
• Porphyria;
• Vaginal bleeding of unknown origin;
• Severe liver disease currently or in history (liver function test indicators have not normalized);
• Benign or malignant liver tumor currently or in history.

The use of Norcolut^® is contraindicated in the presence of hepatitis C and the use of medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir.

If any of the above diseases or conditions occur while using Norcolut^®, the patient should immediately contact the attending physician.

Use in Pregnancy and Lactation

In case of planned or established pregnancy, the use of Norcolut^® is contraindicated.

When using norethisterone in the postpartum period, the drug may affect lactation, reducing the quantity and quality of breast milk.

Use in Hepatic Impairment

The efficacy and safety of norethisterone in patients with hepatic impairment have not been studied. However, as with all sex hormones, the use of norethisterone in patients with severe hepatic impairment is contraindicated.

Use in Renal Impairment

The efficacy and safety of norethisterone in patients with renal impairment have not been studied.

Pediatric Use

Contraindicated during puberty.

Geriatric Use

Use of Norcolut^® in elderly patients is not indicated.

Special Precautions

Before starting treatment, it is necessary to exclude the presence of malignant neoplasms, conduct a preliminary thorough gynecological, oncological examination, and breast examination.

Ethinylestradiol is an active metabolite of norethisterone, therefore, when prescribing it, general precautions that must be observed when using combined hormonal contraceptives (COCs) containing ethinylestradiol should also be taken into account.

Use of Norcolut^® should be stopped immediately in the following cases

• Appearance of signs of thromboembolic complications;
• Migraine or frequent unusually severe headache;
• Sudden disturbances of vision, hearing, and speech;
• Increased frequency of epileptic seizures;
• Clinically significant increase in blood pressure;
• Liver enlargement with suspicion of liver tumor development, appearance of jaundice, generalized itching, or development of hepatitis.

The patient should inform the doctor about the following conditions or diseases that existed before taking Norcolut^®, occurred for the first time, or worsened during drug use

• Breast cancer in a close relative of the patient currently or in history;
• Hereditary angioedema – drugs containing estrogens can provoke or worsen symptoms of angioedema. A doctor should be consulted immediately if symptoms of angioedema appear, such as swelling of the face, tongue and/or pharynx, difficulty swallowing, or urticaria combined with difficulty breathing;
• Heart and vascular disease;
• Diabetes mellitus;
• Kidney disease;
• Hepatitis and liver function disorders;
• Bronchial asthma;
• Epilepsy;
• Pituitary tumor (prolactinoma);
• Predisposition to thrombosis;
• Crohn’s disease or ulcerative colitis;
• Systemic lupus erythematosus;
• Hemolytic-uremic syndrome;
• Sickle cell anemia;
• Hypertriglyceridemia (including indication in family history). Hypertriglyceridemia is associated with an increased risk of pancreatitis;
• If surgical operation is necessary or prolonged immobilization;
• Early postpartum period, as there is an increased risk of thrombosis. The patient should be advised when Norcolut^® can be started after childbirth;
• Superficial vein thrombophlebitis;
• Varicose veins;
• Chloasma (including history of chloasma of pregnancy). In this case, the patient is recommended to avoid exposure to direct sunlight or UV radiation;
• If a disease that first appeared during pregnancy or against the background of previous use of sex hormones (for example, hearing loss, porphyria, herpes gestationis, Sydenham’s chorea, cholestatic jaundice and/or itching associated with cholestasis, gallstone formation);
• Increased ALT activity during therapy for viral hepatitis C (with a combination of medicinal products containing ombitasvir, paritaprevir, ritonavir, dasabuvir with or without ribavirin).

How to recognize thrombosis

If any of the signs or symptoms listed below occur, seek medical attention immediately.

Venous thrombosis

If a blood clot forms in a vein of the leg or foot, it can cause deep vein thrombosis (DVT).

If a blood clot migrates from the leg vessels and lodges in the lung vessels, it can cause pulmonary embolism (PE).

Very rarely, a blood clot can form in the vessels of another organ, for example, the eye (retinal vein thrombosis).

The overall risk of developing DVT or PE while taking Norcolut^® is low.

The risk of thrombosis may vary depending on the presence and severity of individual risk factors for thrombosis development.

Factors increasing the risk of venous thrombosis/venous thromboembolism (VTE)

• Obesity (BMI over 30 kg/m²);
• Family history of venous thrombosis or thromboembolism in siblings or parents under the age of 50 (in case of hereditary predisposition, consult a specialist before starting the drug);
• Prolonged immobilization, major surgical interventions; surgical interventions on the lower limbs, pelvic area; neurosurgical operative interventions; extensive trauma. In these situations, COC use should be discontinued (in case of planned surgery, at least 4 weeks before it) and not resumed for 2 weeks after full recovery of mobility. If discontinuation of Norcolut^® is required, the doctor should advise when it can be resumed;
• Age over 35 years;
• Period of several weeks after childbirth;
• Temporary immobilization (for example, an airplane flight lasting more than 4 hours) may also be a risk factor for VTE, especially in the presence of other risk factors.

The more risk factors a patient has, the higher the likelihood of blood clots forming.

Flights (>4 hours) can temporarily increase the risk of thrombosis, especially if you have other risk factors listed above.

The doctor should be informed if any risk factors have arisen or changed during drug use, for example, a significant increase in body weight, a close relative developed thrombosis for an unknown reason.

Arterial thrombosis

Arterial thrombosis can cause myocardial infarction or stroke.

It is important to note that the risk of developing myocardial infarction or stroke while taking Norcolut^® is low but may increase.

Risk factors for arterial thrombosis:

• Age over 35 years;
• Smoking (women over 35 years of age who have not quit smoking are strongly advised to choose other methods of contraception);
• Arterial hypertension;
• Obesity (BMI over 30 kg/m²);
• Family history of arterial thrombosis or thromboembolism in siblings or parents under 50 years of age;
• Hypercholesterolemia or hypertriglyceridemia, including in family history;
• Migraine, especially migraine with aura;
• Heart valve disease, atrial fibrillation;
• Diabetes mellitus.

If more than one of the listed diseases or conditions is present, the risk of arterial thrombosis increases.

You should inform your doctor if any risk factors have appeared or changed during the use of the drug, for example, a significant increase in body weight is observed, or a close relative has developed thrombosis for an unknown reason.

Laboratory Tests

Taking sex hormones may affect the results of some laboratory tests, including biochemical parameters of liver, thyroid, adrenal, and kidney function, the concentration of transport proteins in plasma (e.g., transcortin, lipid/lipoprotein fractions, parameters of carbohydrate metabolism, coagulation, and fibrinolysis). These changes generally remain within normal physiological limits.

The drug contains lactose monohydrate, therefore patients with rare hereditary galactose intolerance, lactase deficiency, or glucose/galactose malabsorption should not take this drug.

Effect on the Ability to Drive Vehicles and Operate Machinery

Norethisterone does not affect the ability to drive vehicles or operate machinery.

Overdose

Symptoms due to the low toxicity of norethisterone, acute toxic effects are not expected in case of overdose. No serious side effects have been reported after young children ingested high doses of norethisterone (as a combined oral contraceptive containing Norethisterone).

Overdose may cause nausea and withdrawal bleeding in women.

Treatment symptomatic therapy is performed.

Drug Interactions

Some drugs may affect the concentration of norethisterone in the blood, their use may reduce effectiveness and lead to the development of sudden bleeding, including barbiturates, carbamazepine, phenytoin, primidone, oxcarbazepine, felbamate, topiramate, rifampicin, protease inhibitors and non-nucleoside reverse transcriptase inhibitors, for example, ritonavir, nevirapine, efavirenz, griseofulvin, bosentan, herbal preparations of St. John’s wort.

Some drugs may increase the plasma concentration of norethisterone, which may lead to an increase in the frequency or severity of adverse reactions: itraconazole, voriconazole, fluconazole; verapamil; clarithromycin, erythromycin; diltiazem.

When Norcolut^® is taken concomitantly with grapefruit juice, an increase in the frequency or severity of adverse reactions is also possible.

Norcolut^® may affect the effects of other drugs, for example, cyclosporine (a drug used to prevent tissue rejection after transplantation); the antiepileptic drug lamotrigine (concomitant use with this drug may lead to an increased frequency of epileptic seizures).

The use of Norcolut^® is contraindicated during therapy with drugs for the treatment of hepatitis C containing ombitasvir/paritaprevir/ritonavir and dasabuvir, since concomitant use may lead to increased liver enzyme activity (increased ALT activity).

Storage Conditions

The drug should be stored out of the reach of children at a temperature between 15°C (59°F) and 30°C (86°F).

Shelf Life

The shelf life is 5 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

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.