Cyclo-Progynova^® (Tablet kit) Instructions for Use

Marketing Authorization Holder

Bayer, AG (Germany)

Manufactured By

Bayer Weimar, GmbH & Co. KG (Germany)

ATC Code

G03FB01 (Norgestrel and estrogen)

Active Substances

Estradiol valerate (Rec.INN registered by WHO)

Norgestrel (Rec.INN registered by WHO)

Dosage Form

Cyclo-Progynova®

Coated tablet set: 21 pcs. in a box, incl.: white tab. 2 mg: 11 pcs., light brown tab. 0.5 mg+2 mg: 10 pcs.

Dosage Form, Packaging, and Composition

A set of coated tablets, of two types.

White coated tablets, round, biconvex (11 pcs. in a blister).

Excipients: lactose monohydrate, corn starch, povidone 25 thousand, talc, magnesium stearate, sucrose, povidone 90 thousand, macrogol 6000, calcium carbonate, talc, glycol montan wax.

Light brown coated tablets, round, biconvex (10 pcs. in a blister).

Excipients: lactose monohydrate, corn starch, povidone 25 thousand, talc, magnesium stearate, sucrose, povidone 90 thousand, macrogol 6000, calcium carbonate, talc, glycerol 85%, glycol montan wax, titanium dioxide (E171), iron oxide yellow dye (E172), iron oxide red dye (E172).

21 pcs. (10 and 11 pcs.) – blisters (1) with a self-adhesive intake calendar – cardboard boxes with first opening control.

Clinical-Pharmacological Group

Anticlimacteric drug

Pharmacotherapeutic Group

Combined antimenopausal agent (estrogen + progestogen)

Pharmacological Action

A combined hormonal drug containing an estrogen and a progestogen.

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

Norgestrel is a progesterone derivative.

The addition of norgestrel for 10 days of each cycle prevents the development of endometrial hyperplasia and cancer.

Due to the composition and cyclic regimen of this combination (estrogen-only intake for 11 days, then a combination of estrogen and progestogen for 10 days, and finally a 7-day break), a menstrual cycle is established in women with an intact uterus with regular use of the drug.

Against the background of taking this combination, ovulation is not suppressed, and the body’s own hormone production is practically unchanged.

Estradiol replenishes the deficiency of estrogens in the female body after menopause and provides effective treatment of psychoemotional and autonomic menopausal symptoms (such as “hot flashes”, increased sweating, sleep disturbance, 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 genitourinary 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 hormone replacement therapy (HRT) has been proven to reduce the risk of peripheral bone fractures in postmenopausal women. When HRT is discontinued, 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, as well as on its density, and can also slow down the process of wrinkle formation.

HRT leads to a decrease in the level of total cholesterol, LDL and an increase in HDL cholesterol, as well as an increase in the level of triglycerides. The progestogen contained in this combination, to a certain extent, counteracts the effect of estradiol on lipid metabolism.

Pharmacokinetics

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 3%. Food intake does not affect the bioavailability of estradiol. The C_max of estradiol in serum, which is approximately 30 pg/ml, is usually reached 4-9 hours after taking this combination in a single dose. Estradiol is excreted as metabolites, mainly in the urine as sulfates and glucuronides.

After oral administration, norgestrel is rapidly and almost completely absorbed from the gastrointestinal tract. The C_max of levonorgestrel in serum, which is approximately 7-8 pg/ml, is usually reached 1-1.5 hours after taking the tablet. Levonorgestrel binds to albumin and sex hormone-binding globulin (SHBG). About 1-1.5% of the total concentration of levonorgestrel in serum is not bound to protein. The T_1/2 of norgestrel metabolites is 1 day. Norgestrel metabolites are excreted in the urine and bile.

Indications

Hormone replacement therapy for menopausal disorders, involutional changes of the skin and urinary tract and genital tract, depressive states in the menopausal 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

Take orally, swallowed whole with water.

Follow the sequential order of tablets as indicated on the blister pack calendar.

Initiate therapy with one white tablet containing 2 mg estradiol valerate daily for 11 consecutive days.

Subsequently, take one light brown tablet containing 2 mg estradiol valerate and 0.5 mg norgestrel daily for the next 10 consecutive days.

After completing the 21-day tablet course, take a 7-day treatment-free break.

During this treatment-free interval, withdrawal bleeding usually occurs.

Begin the next treatment cycle with a white tablet on the eighth day after the last light brown tablet, irrespective of bleeding.

For women with an intact uterus not currently undergoing menstruation, start treatment on any convenient day.

For women switching from another sequential HRT product, begin Cyclo-Progynova the day after completing the previous cycle.

For the treatment of irregular menstrual cycles, start on the fifth day of the cycle.

For the treatment of secondary amenorrhea, a progestogen challenge test is recommended prior to initiation.

If a tablet is missed and remembered within 12 hours, take it immediately and continue the schedule.

If a tablet is missed for more than 12 hours, discard the missed tablet and continue the schedule; contraception is not assured.

In case of breakthrough bleeding or spotting during the first half of the cycle, continue treatment as scheduled.

If breakthrough bleeding occurs in the second half of the cycle, continue treatment until finish and consider increasing the progestogen dose in the next cycle if bleeding persists.

If irregular bleeding persists or occurs after previously regular cycles, conduct diagnostic evaluation to rule out malignancy.

Periodically re-evaluate the risk-benefit ratio for continued therapy.

Adverse Reactions

From the reproductive system and mammary glands 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.

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

From the skin and subcutaneous tissue skin rash, skin itching, chloasma, erythema nodosum.

From the nervous system headache, migraine, dizziness, anxiety or depressive symptoms, increased fatigue.

From the cardiovascular system tachycardia, increased blood pressure.

From the blood coagulation system venous thrombosis and thromboembolism.

Other edema, muscle cramps, changes in body weight, changes in libido, visual disturbances, contact lens intolerance, allergic reactions.

Contraindications

Hypersensitivity to the components of the combination; pregnancy, breastfeeding period; 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; liver tumors currently or in history (benign or malignant); severe liver diseases; acute arterial thrombosis or thromboembolism (such as myocardial infarction, stroke); acute deep vein thrombosis, thromboembolism currently or in history; severe hypertriglyceridemia.

With caution

Arterial hypertension; congenital hyperbilirubinemias (Gilbert, Dubin-Johnson and Rotor syndromes); cholestatic jaundice or cholestatic itching during pregnancy; endometriosis; uterine fibroids; diabetes mellitus.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

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

Use in Hepatic Impairment

Contraindicated in liver tumors currently or in history (benign or malignant); in severe liver diseases.

Use in Renal Impairment

Taking sex steroids may affect biochemical parameters of kidney function.

Pediatric Use

Not used in children.

Geriatric Use

Use with caution to avoid the risk of exacerbation of chronic diseases.

Special Precautions

This combination is not used for contraception.

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

A number of controlled randomized, as well as epidemiological studies have revealed an increased relative risk of developing venous thromboembolism (VTE) against the background of HRT, i.e., deep vein thrombosis or pulmonary embolism. Therefore, when prescribing HRT to women with VTE risk factors, the risk-benefit ratio of treatment should 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, major planned and trauma surgeries, or massive trauma. Depending on the cause or duration of immobilization, the advisability of temporarily stopping HRT should be decided.

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

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

According to clinical trials and observational studies, an increased relative risk of developing breast cancer was found in women using 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 and may increase 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, as well as with obesity and alcohol abuse. The increased risk gradually decreases to the usual level during the first few years after stopping HRT.

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

Against the background of the use of sex steroids, which include HRT drugs, benign, and even less often, malignant liver tumors have been rarely observed. In some cases, these tumors led to life-threatening intra-abdominal bleeding. For pain in the upper abdomen, enlarged liver, or signs of intra-abdominal bleeding, the possibility of a liver tumor should be considered in the differential diagnosis.

Estrogens are known to increase the lithogenicity of bile. Some women are predisposed to the development of cholelithiasis during treatment with estrogens.

Treatment should be stopped immediately if migrainous or frequent and unusually severe headaches occur for the first time, as well as if other symptoms appear – possible precursors of thrombotic stroke of the brain.

In case of mild liver dysfunction, 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 itching, observed for the first time during pregnancy or previous treatment with sex steroid hormones, HRT should be stopped immediately.

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

Although HRT can affect peripheral insulin resistance and glucose tolerance, there is usually no need to change the treatment regimen for patients with diabetes when using HRT. Nevertheless, women with diabetes should be under supervision 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, uterine fibroids may increase in size. In this case, treatment should be discontinued.

It is recommended to stop treatment if endometriosis recurs during HRT.

If 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 conditions may occur or worsen during HRT. Although their relationship with HRT has not been proven, women with these conditions should be under medical supervision during HRT: epilepsy; benign breast tumor; bronchial asthma; migraine; porphyria; otosclerosis; systemic lupus erythematosus, chorea minor.

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

Drug Interactions

Long-term treatment with drugs that induce liver enzymes (for example, some anticonvulsants and antimicrobials) may increase the clearance of sex hormones and reduce their clinical effectiveness. A similar property of inducing liver enzymes has been found in hydantoins, barbiturates, primidone, carbamazepine and rifampicin; the presence of this feature is also assumed for oxcarbazepine, topiramate, felbamate and griseofulvin. Maximum enzyme induction is usually observed no earlier than 2-3 weeks, but then it can persist for at least another 4 weeks after discontinuation of the drug.

In rare cases, a decrease in estradiol levels has been observed against the background of concomitant use of some antibiotics (for example, penicillin and tetracycline groups).

Substances that are largely subject to conjugation (for example, 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, in some cases, the need for oral antidiabetic agents or insulin may change.

Excessive alcohol consumption during HRT may lead to an increase in the concentration of circulating estradiol.

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.