Norkolut

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NORKOLUT® (NORCOLUT®)

Composition:

Active substance: norethisterone; 17α-ethinyl-17β-hydroxy-4-estren-3-one;

1 tablet contains 5 mg of norethisterone;

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

Pharmaceutical form. Tablets.

Main physicochemical properties: flat, round tablets of white or almost white color, with a bevel; on one side of the tablet – the marking «NORCOLUT», on the other – «+»; diameter: approximately 8 mm.

Pharmacotherapeutic group. Sex gland hormones and drugs used in pathologies of the reproductive system. Progestogens.

ATC code G03DC02.

Pharmacological properties.

Pharmacodynamics.

Norethisterone is a progestogen. It induces secretory changes in the proliferating endometrium and suppresses gonadotropin secretion in the pituitary gland, thereby inhibiting follicular maturation and preventing ovulation.

Pharmacokinetics.

Absorption

Well absorbed from the gastrointestinal tract. Due to extensive first-pass metabolism in the liver and intestinal wall, bioavailability ranges from 50% to 77%.

Distribution

After administration of 0.5 mg, 1 mg, or 3 mg of norethisterone, peak plasma concentrations reach 2–5 ng/mL, 5–10 ng/mL, or 30 ng/mL, respectively, measured 0.5–4 hours after drug intake. When administered in combination with ethinylestradiol, an increase in plasma concentration of the drug may occur, rising with repeated administration until steady-state conditions are achieved. This is primarily due to norethisterone binding to sex hormone-binding globulin (SHBG) and a consequent slowing of its metabolism.

Biological transformation

Among norethisterone metabolites, numerous isomers are present, such as 5α-dihydronorethisterone and tetrahydro-norethisterone, which are excreted in urine as glucuronide conjugates. Some portion of norethisterone and its metabolites form a bond with the 17β-hydroxy group.

Elimination

Decline in norethisterone concentration in blood serum occurs in two phases. The elimination half-life is 2.5 hours in the first phase and 8 hours in the terminal phase. Approximately 80% of metabolites formed in the liver are excreted in urine.

Clinical characteristics.

Indications.

Secondary amenorrhea, endometriosis.

Contraindications.

Norcolut® must not be used in the presence of any of the following conditions or diseases listed below.

• Pregnancy or suspected pregnancy.
• Breastfeeding.
• Presence or risk of venous thromboembolism (VTE).
• Current venous thromboembolism (during anticoagulant therapy) or history of VTE [e.g., deep vein thrombosis (DVT) or pulmonary embolism (PE)].
• Known hereditary or acquired predisposition to venous thromboembolism, such as activated protein C resistance (including factor V Leiden mutation), antithrombin III deficiency, protein C deficiency, protein S deficiency.
• Major surgery with prolonged immobilization (see section "Special precautions").
• High risk of venous thromboembolism due to the presence of multiple risk factors (see section "Special precautions").
• Presence or risk of arterial thromboembolism (ATE).
• Current arterial thromboembolism, history of arterial thromboembolism (e.g., myocardial infarction), or prodromal conditions (e.g., angina pectoris).
• Cerebrovascular disorders – current stroke, history of stroke, or prodromal conditions [e.g., transient ischemic attack (TIA)].
• Established hereditary or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinemia and presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).
• History of migraine with focal neurological symptoms.
• High risk of arterial thromboembolism due to multiple risk factors (see section "Special precautions") or presence of any of the following serious risk factors:
  • diabetes mellitus with vascular complications;
  • severe arterial hypertension;
  • severe dyslipoproteinemia.
• Dubin-Johnson syndrome, Rotor syndrome, as well as cholestasis or severe pruritus during previous pregnancies.
• Previous occurrence of pemphigoid gestationis (herpes gestationis).
• Benign or malignant liver tumors, current or past.
• Current or past hormone-dependent malignant neoplasms (e.g., of the breast or genital organs).
• Vaginal bleeding of unknown etiology.
• Untreated endometrial hyperplasia.
• Hypersensitivity to norethisterone or to any of the excipients of the drug.

Norcolut® is contraindicated for concomitant use with medicinal products containing ombitasvir/paritaprevir/ritonavir, dasabuvir, glecaprevir/pibrentasvir, or sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction").

If any of the above conditions develops for the first time during treatment with Norcolut®, the drug should be discontinued immediately and medical advice should be sought.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on Norcolut®

An interaction with medicinal products that induce microsomal enzymes is possible, leading to increased clearance of sex hormones, which may result in menstrual bleeding and/or contraceptive failure.

Enzyme induction may occur within a few days of starting treatment. Maximum enzyme induction is usually observed within several weeks. After discontinuation of the inducing agent, enzyme induction may persist for up to 4 weeks.

Substances that increase the clearance of sex hormones (reduced efficacy of COCs [combined oral contraceptives] due to enzyme induction) include: phenytoin, barbiturates, bosentan, primidone, carbamazepine, rifampicin, ritonavir, nevirapine, efavirenz, and possibly oxcarbazepine, topiramate, felbamate, griseofulvin, and herbal products containing St. John’s wort (Hypericum perforatum).

Substances with variable effects on sex hormone clearance

When co-administered with sex hormones, many HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors may increase or decrease plasma concentrations of estrogens or progestins. The clinical significance of these changes may be relevant in some cases.

Substances that reduce COC clearance (enzyme inhibitors)

The clinical significance of potential interactions with enzyme inhibitors remains unclear. Potent and moderate CYP3A4 inhibitors such as azole antifungals (itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g., clarithromycin, erythromycin), diltiazem, and grapefruit juice may lead to increased serum concentrations of estrogens and/or progestins. Etoricoxib at doses of 60 to 120 mg/day has been shown to increase plasma concentrations of ethinylestradiol by 1.4–1.6 times when co-administered with a combined hormonal medicinal product containing 0.035 mg ethinylestradiol.

Effect of Norcolut® on other medicinal products

Progestogens may affect the metabolism of other medicinal products, resulting in increased (e.g., cyclosporine) or decreased (e.g., lamotrigine) concentrations in plasma and tissues. Based on clinical data, ethinylestradiol is thought to inhibit the clearance of CYP1A2 substrates, leading to mild (e.g., with theophylline) or moderate (e.g., with tizanidine) increases in their plasma concentrations.

Pharmacodynamic interactions

During clinical trials in patients receiving antiviral therapy for hepatitis C virus (HCV) infection containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, increased transaminase levels (ALT [alanine aminotransferase]) more than 5 times the upper limit of normal were observed. This occurred significantly more often in women receiving medicinal products containing ethinylestradiol, including combined hormonal contraceptives (COCs). Similarly, increased ALT levels were observed in women taking ethinylestradiol-containing medicinal products, such as COCs, when treated with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section "Contraindications"). Treatment with Norcolut® may be resumed 2 weeks after completion of therapy with these combination regimens.

Warning: To identify potential drug interactions, information contained in the package leaflets of other concurrently administered medicinal products should be considered.

Special precautions for use.

To prevent pregnancy, non-hormonal methods of contraception (barrier methods) must be used.

Additional warnings regarding partial conversion of norethisterone to ethinylestradiol.

Norethisterone is partially metabolized to ethinylestradiol; thus, from each milligram of orally administered norethisterone / norethisterone acetate, an amount of ethinylestradiol is formed equivalent to an oral dose of approximately 4–6 µg in humans (see section “Pharmacokinetics”).

Due to the partial conversion of norethisterone to ethinylestradiol, the use of Norcolut® may produce pharmacological effects similar to those observed with combined oral contraceptives (COCs). Therefore, the general warnings associated with COC use, listed below, should be taken into consideration.

Before initiating or continuing treatment with Norcolut®, an individual risk/benefit assessment must be performed if any of the disorders/factors listed below are present or worsening.

Vascular disorders

Venous thromboembolism (VTE).

The use of combined hormonal contraceptives (CHCs) increases the risk of venous thromboembolism (VTE) in users compared to non-users. The risk of VTE varies depending on the type of progestogen contained in different CHCs. Based on current data, CHCs containing progestogens such as levonorgestrel, norgestimate, or norethisterone are associated with a lower risk of VTE.

Approximately 5–7 out of 10,000 women using CHCs containing levonorgestrel, norgestimate, or norethisterone will develop a thrombosis each year.

When prescribing CHCs, existing risk factors in women, particularly those predisposing to VTE, should be carefully evaluated, and the risks associated with different medicinal products should be compared. CHCs are contraindicated if a woman has any major risk factors for thrombus formation.

Treatment should be discontinued immediately if symptoms suggestive of thromboembolic complications occur. The need for continued therapy should be reassessed before reinitiating treatment.

The likelihood of developing venous thromboembolic complications while using sex hormones is significantly increased in women with additional risk factors, especially multiple ones (see Table 1).

Norcolut® is contraindicated in women with multiple risk factors that place them in a high-risk category for venous thrombosis (see section “Contraindications”). If a woman has more than one risk factor, the overall risk will be greater than the sum of the risks associated with each individual factor—therefore, the total risk of VTE should be considered. Norcolut® should not be prescribed if the benefit-risk ratio is judged to be unfavorable (see section “Contraindications”).

Well-established risk factors for venous thromboembolism (VTE) include:

Table 1

Risk factors for VTE

Symptoms of deep vein thrombosis (DVT) may include:

• unilateral swelling of the leg and/or foot or along a vein in the leg;
• pain or increased tenderness in the leg, which may occur only when standing or walking;
• a sensation of warmth in the affected leg; redness or discoloration of the skin on the leg.

Symptoms of pulmonary embolism (PE) may include:

• sudden shortness of breath of unknown cause or rapid breathing;
• sudden cough, possibly with blood;
• acute chest pain;
• fainting or dizziness;
• rapid or irregular heartbeat.

Some of these symptoms (e.g., shortness of breath, cough) are nonspecific and may be mistakenly interpreted as more common or less severe conditions (e.g., respiratory tract infections).

Other signs of vascular occlusion may include: sudden pain, swelling, and mild bluish discoloration of a limb.

In the case of occlusion of an ocular vessel, symptoms may include blurred vision without pain, which may progress to vision loss. Sometimes, vision loss develops almost immediately.

Arterial thromboembolism (ATE).

Epidemiological studies associate the use of sex hormones with an increased risk of arterial thromboembolism (myocardial infarction) or cerebrovascular events (e.g., transient ischemic attack, stroke). Arterial thromboembolism can lead to fatal outcomes.

Risk factors for ATE

The likelihood of developing arterial thromboembolic complications or cerebrovascular events while using sex hormones increases in women with risk factors (see Table 2). The medicinal product Norcolut® is contraindicated in women with one serious risk factor or multiple risk factors for ATE, placing them in a high-risk group for arterial thrombosis (see section «Contraindications»). If a woman has more than one risk factor, the increase in risk is greater than the sum of the risks associated with each individual factor, so the overall risk should be considered. Norcolut® should not be prescribed if the benefit-risk ratio is considered negative (see section «Contraindications»).

Table 2

Risk factors for ATE

ATE Symptoms

Women should be informed that if symptoms occur, they should seek immediate medical attention and inform the healthcare provider about the use of Norcolut®.

Symptoms of cerebrovascular disorders may include:

• sudden weakness or numbness of the face, leg, or arm, especially on one side of the body;
• sudden difficulty walking, dizziness, loss of balance, or coordination;
• sudden confusion, speech disturbances, or difficulty understanding speech;
• sudden vision impairment in one or both eyes;
• sudden severe or prolonged headache without a known cause;
• loss of consciousness or fainting with or without seizures.

Transient nature of symptoms suggests transient ischemic attack (TIA).

Symptoms of myocardial infarction (MI) may include:

• pain, discomfort, pressure, heaviness, squeezing, or aching sensation in the chest, arm, or behind the breastbone;
• discomfort radiating to the back, lower jaw, throat, arm, or stomach;
• feeling of fullness, indigestion, or suffocation;
• excessive sweating, nausea, vomiting, or dizziness;
• severe weakness, anxiety, or shortness of breath;
• rapid or irregular heartbeat.

Tumors

Isolated cases of benign liver tumors and even rarer cases of malignant tumors have been reported in patients receiving hormonal substances contained in Norcolut®. In some cases, these tumors led to life-threatening intra-abdominal hemorrhage.

If women receiving COCs experience severe pain in the upper abdomen, signs of liver enlargement, or signs of intra-abdominal bleeding, the liver should be examined for the presence of a tumor.

Cervical cancer

The most important risk factor for cervical cancer is persistent human papillomavirus (HPV) infection. Some epidemiological studies have indicated that long-term use of COCs may increase this risk. However, this assertion remains controversial, as it is not fully established to what extent study results accounted for confounding factors such as frequency of cervical screening and sexual behavior, including use of barrier contraception methods.

Breast cancer

A meta-analysis of 54 epidemiological studies indicates a slight increase in relative risk (RR = 1.24) of developing breast cancer in women using COCs. This increased risk gradually disappears within 10 years after discontinuation of COC use. Since breast cancer is rare in women under 40 years of age, the increase in incidence among women currently or recently using COCs is small compared to the overall risk of breast cancer. The results of these studies do not provide evidence of a causal relationship. The observed increased risk may be due to earlier diagnosis of breast cancer in COC users, a biological effect of COCs, or a combination of both factors. It has been noted that breast cancer diagnosed in women who have ever used COCs is generally less clinically advanced than in those who have never used COCs.

Malignant tumors can be life-threatening or lead to fatal outcomes. Immediate medical consultation is required if severe abdominal pain occurs for the first time.

Other diseases

Patients with diabetes should be under close medical supervision.

Chloasma may occur in isolated cases, particularly in women with a history of chloasma during pregnancy. Women prone to chloasma should avoid exposure to sunlight or ultraviolet radiation during treatment.

In cases of acute visual disturbances, exophthalmos, diplopia, or migraine, papilledema or retinal disorders should be ruled out.

Patients with a history of depression should be closely monitored by physicians. The drug should be discontinued if depression worsens.

Progestogens may cause fluid retention. Use with caution in patients with epilepsy, migraine, asthma, or cardiac dysfunction.

Use of COCs in women with hypertriglyceridemia or a family history of hypertriglyceridemia may increase the risk of pancreatitis.

Although slight increases in blood pressure have been reported in many women taking COCs, clinically significant elevations are rare. However, if persistent clinically significant hypertension develops during COC use, the physician should discontinue COCs and initiate antihypertensive treatment. If normal blood pressure levels are achieved with antihypertensive therapy, COC use may be resumed if considered appropriate.

The occurrence or exacerbation of the following conditions has been reported during pregnancy and COC use; however, a definitive causal relationship with COC use has not been established:

• jaundice and/or pruritus associated with cholestasis;
• gallstone formation;
• porphyria;
• systemic lupus erythematosus;
• hemolytic-uremic syndrome;
• Sydenham's chorea;
• herpes gestationis;
• hearing loss associated with otosclerosis.

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

Acute or chronic liver function disorders may require temporary discontinuation of COCs until liver function parameters normalize. Recurrence of cholestatic jaundice, which first occurred during pregnancy or previous use of sex steroids, necessitates discontinuation of COCs.

Crohn’s disease and ulcerative colitis have been associated with the use of combined oral contraceptives.

Medical examination, check-up, and physician consultation

Before initiating or resuming treatment with the drug, women should undergo a complete medical examination, including a gynecological examination. Considerations should be given to the requirements outlined in the sections "Contraindications" and "Special precautions for use." Particular attention should be paid during prolonged use in cases of cardiovascular and renal diseases, asthma, epilepsy, predisposition to thrombosis, hepatitis, and renal dysfunction.

Medical examinations, including pelvic examination, should be repeated periodically during treatment. The frequency and type of these examinations depend on individual patient characteristics but must include measurement of blood pressure, breast examination, abdominal and pelvic organ examination, and cervical cytology.

Women should seek medical advice as soon as possible in the following cases:

• any changes in health status, particularly those mentioned in this instruction;
• chest tightness;
• need to use other medications (see also section "Interaction with other medicinal products and other forms of interaction");
• prolonged immobilization or need for surgical intervention (at least 6 weeks before planned surgery);
• unusually heavy vaginal bleeding.

Reasons for immediate discontinuation of treatment

If possible signs of thrombosis appear, tablet use should be discontinued immediately and medical help sought urgently:

• unusual cough;
• chest pain or tightness, regardless of radiation to the left arm;
• shortness of breath;
• new onset of severe headache or migraine, or increased frequency of unusually severe migraine;
• partial or complete loss of vision or diplopia;
• slurred speech;
• sudden disturbances in hearing, smell, or taste;
• dizziness or loss of consciousness;
• weakness or numbness in any part of the body;
• severe pain or swelling in the legs.

Tablet use should also be discontinued and immediate medical help sought in the following cases:

• development of jaundice or hepatitis (non-icteric);
• severe generalized edema;
• high blood pressure;
• pregnancy.

Medical consultation is required if any of the following conditions are present or worsen during treatment. The physician will assess the benefits and risks of initiating or continuing the drug and determine whether close monitoring is necessary:

• smoking;
• diabetes mellitus;
• obesity;
• recent thrombosis/embolism;
• personal or family history of thrombosis (venous thromboembolism in a close relative at a relatively young age);
• personal history of breast cancer;
• personal history or presence of chloasma (yellowish-brown skin pigmentation, especially on the face). In such cases, prolonged exposure to sunlight or ultraviolet radiation should be avoided;
• personal history of depression.

Effect on laboratory test results

Progestogen use may affect the results of certain laboratory tests.

Available data indicate that combined oral contraceptives (COCs) may influence the results of laboratory tests, including liver function, thyroid function, and blood coagulation parameters.

Patients should inform their physician or laboratory personnel about Norcolut® use, as it may affect certain test results.

Warnings regarding excipients

This medicinal product contains lactose. Patients with hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding

Reproductive toxicity studies have shown a risk of virilization of female embryos when high doses are administered during the development of external genital organs. Furthermore, epidemiological studies have demonstrated that this risk is substantial in humans when high doses are used. Norcolut® may cause virilization of female embryos if taken during the period of somatic sexual differentiation, which is characterized by hormonal sensitivity (starting from the 45th day of pregnancy). Apart from the above, no other signs of teratogenic effects have been observed in studies.

When resuming use of sex hormones, the increased risk of VTE in the postpartum period should be considered.

Norcolut® must not be used in pregnant women or in women suspected of being pregnant, or during breastfeeding.

Ability to influence reaction speed when driving vehicles or operating machinery

The drug has not been shown to affect the ability to drive vehicles or operate machinery.

Method of Administration and Dosage

Take tablets whole with liquid, without chewing.

The effectiveness of Norkolut® tablets may be reduced if a patient forgets to take a tablet as directed. The patient should take only the most recently missed tablet as soon as she remembers, then continue taking tablets at the usual time the following day.

If contraception is needed, additional non-hormonal contraceptive methods should be used.

Secondary Amenorrhea

Any hormonal therapy for secondary amenorrhea should only be initiated after pregnancy has been excluded. In some cases, secondary amenorrhea is caused by a prolactinoma, which should be ruled out before starting treatment with Norkolut®.

The physician should first prescribe an estrogen-containing medication (e.g., for 14 days) prior to initiating treatment with Norkolut®. Thereafter, take 1 tablet of Norkolut® 1–2 times daily for 10 days. Withdrawal bleeding usually begins a few days after the last tablet.

Once adequate estrogen production is achieved, estrogen therapy may be discontinued, and cyclic bleeding can be induced by administering 1 tablet of Norkolut® twice daily from day 16 to day 25 of the cycle.

Endometriosis

Begin treatment between day 1 and day 5 of the cycle, using 1 tablet of Norkolut® twice daily. If breakthrough bleeding occurs, the dose should be increased to 2 tablets twice daily. After bleeding stops, the dose may be reduced back to the initial dose. The duration of treatment should be at least 4–6 months. With continuous daily use, ovulation and menstruation are usually absent. Withdrawal bleeding occurs after completion of hormonal therapy.

Children

The drug is not intended for use in children.

Overdose

Acute toxicity studies have not demonstrated a risk of acute adverse reactions following accidental ingestion of doses several times higher than the daily therapeutic dose.

Adverse reactions.

Adverse effects occur more frequently during the first months after starting Norcolut® treatment.

Such adverse events have been reported in patients taking norethisterone, although a causal relationship could not always be established. The adverse reactions listed below are classified according to MedDRA system organ classes. Frequency data are based on post-marketing surveillance studies and scientific literature.

* When used for the indication "Endometriosis".

Frequency unknown (cannot be estimated from the available data) (see details in section "Special precautions"):

• thromboembolism;
• liver tumors leading to intra-abdominal hemorrhage;
• chloasma;
• severe headache and migraine or increased frequency of unusually severe migraine, sudden disturbances in perception, first signs of thrombophlebitis or symptoms of thromboembolism, chest pain and tightness, onset of jaundice, development of hepatitis, skin itching, significant increase in blood pressure;
• occurrence or worsening of symptoms of angioneurotic edema.

Dizziness, worsening of depression, abdominal pain, and cholestasis have also been observed.

Very high doses of Norcolut® may, in individual cases, lead to cholestatic liver disorders.

Shelf life. 5 years.

Storage conditions. Store at temperatures not exceeding 30 °C.

Keep the medicine out of the reach of children!

Packaging. 10 tablets in a blister; 2 blisters in a cardboard pack.

Prescription status. Prescription only.

Manufacturer. JSC "Gedeon Richter".

Manufacturer's address and location of its business operations.
H-1103 Budapest, 19–21 Dénes u., Hungary.