Klimonorm^® (Tablet kit) Instructions for Use

Marketing Authorization Holder

Zentiva, k.s. (Czech Republic)

Manufactured By

Delpharm Lille, SAS (France)

ATC Code

G03FB09 (Levonorgestrel and estrogens)

Active Substances

Levonorgestrel (Rec.INN registered by WHO)

Estradiol (Rec.INN registered by WHO)

Dosage Form

Klimonorm®

Kit of film-coated tablets: 21 pcs in blister, 1 or 3 blisters per pack, incl.: yellow 2 mg tablets: 9 pcs, brown 0.15 mg+2 mg tablets: 12 pcs.

Dosage Form, Packaging, and Composition

Two types of coated tablets.

Round, yellow coated tablets (9 pcs in a blister).

Excipients: yellow iron oxide, purified water, carnauba wax, dextrose (glucose), gelatin, calcium carbonate, potato starch, lactose monohydrate, basic magnesium carbonate, magnesium stearate, macrogol 35,000, povidone K25, sucrose, talc, titanium dioxide.

Round, brown coated tablets (12 pcs in a blister).

Excipients: brown iron oxide, red iron oxide, purified water, carnauba wax, dextrose (glucose), gelatin, calcium carbonate, potato starch, lactose monohydrate, basic magnesium hydroxycarbonate, magnesium stearate, macrogol 35,000, povidone K25, sucrose, talc, titanium dioxide.

21 pcs – blisters (1) – cardboard packs.
21 pcs – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Anticlimacteric drug

Pharmacotherapeutic Group

Combined antimenopausal agent (estrogen + gestagen)

Pharmacological Action

Anticlimacteric combined preparation containing an estrogen and a gestagen.

Estradiol valerate (estrogen) is converted in the human body into the natural 17β-estradiol.

The addition of the gestagen levonorgestrel for 12 days of each cycle prevents the development of endometrial hyperplasia and cancer.

Due to its composition and cyclic administration regimen (estrogen-only intake for 9 days, followed by a combination of estrogen and gestagen for 12 days, and then a 7-day break), a menstrual cycle is established in women with an intact uterus with regular use.

Estradiol compensates for the deficiency of estrogens in the female body after menopause and provides effective treatment of psychoemotional and autonomic climacteric symptoms (such as hot flashes, increased sweating, sleep disturbances, increased nervous excitability, irritability, palpitations, cardialgia, dizziness, headache, decreased libido, muscle and joint pain); involution of the skin and mucous membranes, especially the mucous membranes of the urogenital system (urinary incontinence, dryness and irritation of the vaginal mucosa, pain during sexual intercourse).

Estradiol prevents bone loss caused by estrogen deficiency. This is mainly due to the suppression of osteoclast function and a shift in the bone remodeling process towards bone formation. Long-term use of HRT has been proven to reduce the risk of peripheral bone fractures in postmenopausal women. Upon discontinuation of HRT, the rate of bone loss is comparable to the rates characteristic of the period immediately after menopause. It has not been proven that using HRT can restore bone mass to premenopausal levels.

HRT also has a beneficial effect on the collagen content in the skin, on its density, and may slow down the process of wrinkle formation.

Taking the drug helps reduce the level of total cholesterol, LDL and increase HDL, as a result of which the HDL/LDL ratio significantly increases, and also leads to an increase in TG levels.

It is believed that among postmenopausal women, the incidence of colon cancer decreases with the use of HRT. The mechanism of action is still unclear.

Pharmacokinetics

Absorption

After oral administration, Estradiol valerate is rapidly and completely absorbed from the gastrointestinal tract. After entering the body, it is rapidly metabolized to form 17β-estradiol and estrone, which then undergo standard metabolic transformations. After oral administration, the bioavailability of estradiol is about 30%. C_max of estradiol in blood plasma is reached after 2-3 hours, the estrone-estradiol ratio is 4:1.

After oral administration, levonorgestrel is rapidly and almost completely absorbed from the gastrointestinal tract. C_max of levonorgestrel in blood plasma is reached after 1-2 hours.

Distribution

93-95% of levonorgestrel is bound to albumin and sex hormone-binding globulin (SHBG).

Metabolism and Excretion

Estradiol is excreted as metabolites, mainly in the urine (90%) and to a lesser extent in the bile.

Levonorgestrel metabolites are excreted in the urine and bile, mainly as sulfates and glucuronides.

Indications

• Hormone replacement therapy (HRT) for climacteric disorders, involutional changes of the skin and urogenital tract, depressive states in the climacteric period, as well as symptoms of estrogen deficiency due to natural menopause or hypogonadism, sterilization or primary ovarian dysfunction in women with an intact uterus;
• Prevention of postmenopausal osteoporosis;
• Normalization of irregular menstrual cycles;
• Treatment of primary or secondary amenorrhea.

ICD codes

Dosage Regimen

If the menstrual cycle is preserved, treatment should be started on the 5th day of the menstrual cycle (the 1st day of menstrual bleeding corresponds to the 1st day of the menstrual cycle).

In case of amenorrhea or very rare menstruation, as well as in postmenopause, the drug can be started at any time, provided that pregnancy is excluded.

Each package is designed for a 21-day course.

One yellow coated tablet is taken daily for the first 9 days, and then one brown coated tablet is taken daily for the next 12 days. After a 21-day course of the drug, a 7-day break in taking the drug follows, during which withdrawal bleeding occurs (usually on the 2nd-3rd day after taking the last coated tablet).

After a 7-day break in taking the drug, a new package is started, taking the first coated tablet on the same day of the week as the first coated tablet from the previous package.

The coated tablets are swallowed whole with a small amount of liquid. The time of day when a woman takes the drug does not matter; however, if she started taking the coated tablets at a specific time, she should adhere to this time in the future. If a woman forgot to take a coated tablet, she can take it within the next 12-24 hours. If the treatment is interrupted for a longer period, vaginal bleeding may occur.

Adverse Reactions

From the reproductive system: changes in the frequency and intensity of uterine bleeding, breakthrough bleeding, intermenstrual spotting (usually weakening during therapy), dysmenorrhea, changes in vaginal discharge, a condition similar to premenstrual syndrome; soreness, tension and/or enlargement of the mammary glands, changes in libido.

From the digestive system: dyspepsia, bloating, nausea, vomiting, abdominal pain, recurrence of cholestatic jaundice are possible.

From the CNS: sometimes – headache, migraine, dizziness, anxiety or depressive symptoms, increased fatigue.

From the cardiovascular system: sometimes – palpitations, increased blood pressure, venous thrombosis and thromboembolism.

From metabolism: edema, changes in body weight are possible.

Dermatological reactions: sometimes – skin rash, skin itching, chloasma, erythema nodosum.

Other: muscle cramps, visual disturbances, contact lens intolerance, allergic reactions.

Contraindications

• Pregnancy;
• Lactation;
• Vaginal bleeding of unknown origin;
• Confirmed or suspected diagnosis of breast cancer;
• Confirmed or suspected diagnosis of hormone-dependent precancerous disease or hormone-dependent malignant tumor;
• Current or history of liver tumors (benign or malignant);
• Severe liver diseases;
• Acute arterial thrombosis or thromboembolism (such as myocardial infarction, stroke);
• Acute deep vein thrombosis, current or history of thromboembolism;
• Severe hypertriglyceridemia;
• Hypersensitivity to the components of the drug.

If any of the above conditions occur during HRT, the use of the drug should be stopped immediately.

Use with caution in patients with arterial hypertension, congenital hyperbilirubinemia (Gilbert’s, Dubin-Johnson and Rotor syndromes), cholestatic jaundice or cholestatic pruritus during pregnancy, with endometriosis, uterine fibroids, diabetes mellitus.

Use in Pregnancy and Lactation

HRT is not performed during pregnancy and lactation.

Large-scale epidemiological studies of steroid hormones used for contraception or HRT have not revealed an increased risk of congenital defects in children born to women who took these hormones before pregnancy, nor a teratogenic effect of hormones when accidentally taken in early pregnancy.

A small amount of sex hormones may be excreted in breast milk.

Use in Hepatic Impairment

Contraindicated in current or history of liver tumors (benign or malignant), severe liver diseases.

Use with caution in patients with cholestatic jaundice or cholestatic pruritus during pregnancy.

In non-severe liver function disorders, including various forms of hyperbilirubinemia such as Dubin-Johnson syndrome or Rotor syndrome, medical supervision and periodic liver function tests are necessary. If liver function parameters worsen, HRT should be discontinued.

Special Precautions

Not intended for contraception.

Before starting or resuming HRT, a woman is recommended to undergo a thorough general medical and gynecological examination (including breast examination and cytological examination of cervical mucus), and to exclude pregnancy. In addition, blood clotting system disorders should be excluded. Periodic follow-up examinations should be carried out.

If contraception is necessary, non-hormonal methods should be used (except for the calendar and temperature methods). If pregnancy is suspected, the intake of coated tablets should be suspended until pregnancy is ruled out.

If any of the conditions or risk factors listed below are present or worsen, the individual risk-benefit ratio of treatment should be assessed before starting or continuing HRT.

Venous Thromboembolism

A number of controlled randomized, as well as epidemiological studies, have revealed an increased relative risk of venous thromboembolism (VTE) during HRT, i.e., deep vein thrombosis or pulmonary embolism. Therefore, when prescribing HRT to women with risk factors for VTE, the risk-benefit ratio of treatment must be carefully weighed and discussed with the patient.

Risk factors for VTE include individual and family history (the presence of VTE in close relatives at a relatively young age may indicate a genetic predisposition) and severe obesity. The risk of VTE also increases with age. The question of the possible role of varicose veins in the development of VTE remains controversial.

The risk of VTE may temporarily increase with prolonged immobilization, extensive planned and trauma surgeries, or massive trauma. Depending on the cause or duration of immobilization, the advisability of temporarily discontinuing HRT should be considered.

Treatment should be stopped immediately if symptoms of thrombotic disorders appear or are suspected.

Arterial Thromboembolism

In randomized controlled trials with long-term use of combined conjugated estrogens and medroxyprogesterone acetate, no evidence of a positive effect on the cardiovascular system was obtained. In large-scale clinical trials of this combination, a possible increase in the risk of coronary heart disease in the first year of use was identified. An increased risk of stroke was also found. To date, no long-term randomized controlled trials have been conducted with other HRT drugs to identify a positive effect on cardiovascular morbidity and mortality rates. Therefore, it is unknown whether this increased risk applies to HRT drugs containing other types of estrogens and progestogens.

Endometrial Cancer

Long-term estrogen monotherapy increases the risk of developing endometrial hyperplasia or carcinoma. Studies have confirmed that the addition of a progestogen reduces the risk of endometrial hyperplasia and cancer.

Breast Cancer

According to clinical trials and observational studies, an increased relative risk of developing breast cancer has been found in women receiving HRT for several years. This may be due to earlier diagnosis, the biological effect of HRT, or a combination of both factors. The relative risk increases with the duration of treatment (by 2.3% with use for one year), possibly increasing even more with the combination of estrogens and progestogens. This increase is comparable to the increase in the risk of breast cancer in women with each year of delay in the onset of natural menopause (by 2.8% per year of delay), as well as with obesity and alcohol abuse. The increased risk gradually decreases to the usual level within the first 5 years after stopping HRT.

According to studies, breast cancer detected in women receiving HRT is usually more differentiated than in women not receiving it.

HRT increases the mammographic density of the mammary glands, which in some cases may negatively affect the radiological detection of breast cancer.

Liver Tumors

During the use of sex steroids, which include HRT agents, benign and, even more rarely, malignant liver tumors have been observed in rare cases. In some cases, these tumors led to life-threatening intraperitoneal bleeding. In case of pain in the upper abdomen, enlarged liver or signs of intraperitoneal bleeding, the possibility of a liver tumor should be considered in the differential diagnosis.

Cholelithiasis

Estrogens are known to increase the lithogenicity of bile. Some women are predisposed to developing gallstones when treated with estrogens.

Other Conditions

Treatment should be stopped immediately if migraine-like or frequent and unusually severe headaches occur for the first time, as well as if other symptoms appear that are possible precursors of a thrombotic stroke.

The relationship between HRT and the development of clinically significant arterial hypertension has not been established. A slight increase in blood pressure has been described in women receiving HRT; clinically significant increases are rare. However, in individual cases, with the development of persistent clinically significant arterial hypertension during HRT, discontinuation of HRT may be considered.

In non-severe liver function disorders, including various forms of hyperbilirubinemia such as Dubin-Johnson syndrome or Rotor syndrome, medical supervision and periodic liver function tests are necessary. If liver function parameters worsen, HRT should be discontinued.

In case of recurrence of cholestatic jaundice or cholestatic pruritus, observed for the first time during pregnancy or previous treatment with sex steroid hormones, HRT should be stopped immediately.

Special observation is required for women with moderately elevated TG levels. In such cases, the use of HRT may cause a further increase in blood TG levels, which increases the risk of developing acute pancreatitis.

Although HRT may affect peripheral insulin resistance and glucose tolerance, there is usually no need to change the treatment regimen for patients with diabetes mellitus during HRT. Nevertheless, patients with diabetes mellitus require observation during HRT.

In some patients, under the influence of HRT, undesirable manifestations of estrogen stimulation may develop, for example, abnormal uterine bleeding. Frequent or persistent abnormal uterine bleeding during treatment is an indication for endometrial examination.

If treatment for irregular menstrual cycles does not produce results, an examination should be performed to rule out an organic disease.

Under the influence of estrogens, an increase in the size of uterine fibroids is possible. In this case, treatment should be discontinued.

It is recommended to stop treatment if a recurrence of endometriosis develops during HRT.

If a prolactinoma is suspected, this disease should be ruled out before starting treatment.

In some cases, chloasma may be observed, especially in women with a history of chloasma of pregnancy. During HRT, women prone to chloasma should avoid prolonged exposure to the sun or UV radiation.

The following diseases and conditions may occur or worsen during HRT: epilepsy, benign breast tumor, bronchial asthma, migraine, porphyria, otosclerosis, systemic lupus erythematosus, Sydenham’s chorea. Although the connection of these diseases and conditions with HRT has not been proven, such patients should be under medical supervision during HRT.

Influence on Laboratory Test Results

Intake of sex steroids can affect biochemical parameters of liver, thyroid, adrenal and kidney function, the plasma concentration of transport proteins such as corticosteroid-binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism, coagulation and fibrinolysis.

Influence on the Ability to Drive Vehicles and Mechanisms

No effect.

Overdose

Acute toxicity studies have not revealed a risk of acute adverse effects following accidental ingestion of Klimonorm^® in an amount significantly exceeding the daily therapeutic dose.

Symptoms: nausea, vomiting, vaginal bleeding are possible.

Treatment: there is no specific antidote, treatment is symptomatic.

Drug Interactions

When starting HRT, the use of hormonal contraceptives must be discontinued. If necessary, the patient should be advised to use non-hormonal contraceptives.

Long-term treatment with drugs that induce liver enzymes (e.g., some anticonvulsants and antimicrobials) may increase the clearance of sex hormones and reduce their clinical efficacy. The ability to induce liver enzymes has been found for hydantoins, barbiturates, primidone, carbamazepine and rifampicin; this property is also suspected for oxcarbazepine, topiramate, felbamate and griseofulvin. Maximum enzyme induction is usually not observed before 2-3 weeks, but may then persist for at least 4 weeks after discontinuation of the drug.

In rare cases, a decrease in estradiol levels has been observed during concomitant administration of certain antibiotics (e.g., penicillins and tetracyclines).

Substances that undergo significant conjugation (e.g., paracetamol) may increase the bioavailability of estradiol due to competitive inhibition of the conjugation system during absorption.

Due to the effect of HRT on glucose tolerance, the need for oral hypoglycemic agents or insulin may change in individual cases.

Excessive alcohol consumption during HRT may lead to increased blood levels of estradiol.

Storage Conditions

The drug should be stored out of the reach of children at room temperature.

Shelf Life

The shelf life is 5 years.

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.