Climen^® (Tablets) Instructions for Use

Marketing Authorization Holder

Zentiva, k.s. (Czech Republic)

Manufactured By

Delpharm Lille, SAS (France)

ATC Code

G03HB01 (Cyproterone and estrogens)

Active Substances

Cyproterone (Rec.INN registered by WHO)

Estradiol valerate (Rec.INN registered by WHO)

Dosage Form

Climen®

Coated tablets, two types: 21 pcs. in a blister, 1 blister in a pack, incl.: white-colored dragees 2 mg: 11 pcs., pink-colored dragees 2 mg+1 mg: 10 pcs.

Dosage Form, Packaging, and Composition

Coated tablets, two types.

White-coated tablets (phase I), round, biconvex; on cross-section: the tablet core is white or almost white, the coating is white (11 pcs. in a blister).

Excipients: lactose monohydrate, corn starch, povidone 25000 (K25), talc, magnesium stearate, sucrose, povidone 700000 (K700), macrogol 6000, calcium carbonate, wax.

Pink-coated tablets (phase II), round, biconvex; on cross-section: the tablet core is white or almost white, the coating is pink (10 pcs. in a blister).

Excipients: lactose monohydrate, corn starch, povidone 25000 (K25), talc, magnesium stearate, sucrose, povidone 700000 (K700), macrogol 6000, calcium carbonate, glycerol 85%, titanium dioxide, iron oxide red, iron oxide yellow, wax.

21 pcs. – blisters (1) – packs.

Clinical-Pharmacological Group

Anticlimacteric drug with antiandrogenic properties

Pharmacotherapeutic Group

Combined antimenopausal agent (cyproterone and estrogens)

Pharmacological Action

The drug contains an estrogen – Estradiol valerate, which is converted in the human body into natural 17β-estradiol. It also contains a progesterone derivative – cyproterone acetate, which has progestogenic, antigonadotropic and antiandrogenic effects.

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

During the use of the drug, ovulation is not suppressed, and the body’s own hormone production is practically unchanged. It can be used by women of reproductive age to regulate the menstrual cycle, as well as by women in perimenopause to treat irregular uterine bleeding.

Estradiol replenishes 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 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 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 fractures in women after menopause. 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, as well as on its density, and can also slow down the process of wrinkle formation.

In addition, due to the antiandrogenic properties of cyproterone acetate, this combination has a therapeutic effect on androgen-dependent diseases such as acne, seborrhea, androgenetic alopecia.

Intake leads to a decrease in the level of total cholesterol, LDL and an increase in HDL, resulting in a significant increase in the HDL/LDL ratio, as well as an increase in triglyceride levels. Due to the lack of androgenic properties, cyproterone acetate practically does not interfere with the effect of estradiol on lipid metabolism.

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

Pharmacokinetics

Estradiol valerate

After oral administration, Estradiol valerate is rapidly and completely absorbed. During absorption and first pass through the liver, the hormone ester is cleaved into estradiol and valeric acid. At the same time, estradiol is largely subject to further metabolism, for example, into estrone, estriol and estrone sulfate. 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 the dragee. 24 hours after administration, the serum estradiol concentration decreases to a concentration of approximately 15 pg/ml. Estradiol binds to albumin and to sex hormone-binding globulin (SHBG). The free fraction of estradiol in serum is approximately 1-1.5%, and the fraction of the substance bound to SHBG is within 30-40%.

The apparent V_d of estradiol after a single intravenous administration is about 1 L/kg.

After hydrolysis of exogenous estradiol valerate, the substance follows the same biotransformation pathways as endogenous estradiol. Estradiol is metabolized mainly in the liver, and also partially in the intestine, kidneys, skeletal muscles and target organs. These processes are accompanied by the formation of estrone, estriol, catecholestrogens, as well as sulfate and glucuronide conjugates of these compounds, all of which have significantly less estrogenic activity or no estrogenic activity at all.

The clearance of estradiol from serum after a single intravenous administration is highly variable in the range of 10 to 30 ml/min/kg. A certain part of estradiol is excreted with bile and undergoes enterohepatic recirculation. Estradiol metabolites are excreted mainly in the urine as sulfates and glucuronides.

The serum estradiol concentration after repeated administration is approximately twice as high as after a single dose. On average, the serum estradiol concentration ranges from 40 pg/L (minimum level) to 90 pg/L (maximum level). The concentration of estrone (a weaker estrogen) is approximately 8 times, and the concentration of estrone sulfate is approximately 150 times higher than the concentration of estradiol. After discontinuation of Climen^®, estradiol and estrone levels return to baseline within two to three days.

Cyproterone acetate

After oral administration in a wide range of doses, cyproterone acetate is rapidly and completely absorbed. The absolute bioavailability after oral administration is 88%.

The C_max of cyproterone acetate in serum, which is about 30 ng/ml, is reached 1-2 hours after a single dose of 1 mg of cyproterone acetate.

Cyproterone acetate binds almost exclusively to serum albumin. About 3.5-4% of the total serum cyproterone acetate concentration is not protein-bound. Since plasma protein binding is non-specific, changes in SHBG levels do not affect the pharmacokinetics of cyproterone acetate. Cyproterone acetate is metabolized by various pathways, including hydroxylation and conjugation. The main metabolite in human serum is the 15β-hydroxy derivative.

The clearance of cyproterone acetate from serum is 3.6 ml/min/kg. Some part of the administered dose is excreted unchanged in the bile. Most of the dose is excreted as metabolites in urine and bile in a ratio of 3:7, T_1/2 1.9 days. Metabolites are eliminated from serum with a similar T_1/2 of 1.7 days.

Due to the long T_1/2 of cyproterone acetate from serum, it can be expected that the serum cyproterone acetate concentration will increase by 2-2.5 times during one treatment cycle.

Indications

HRT for climacteric disorders, involutional changes in 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

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

Follow the sequential order of the blister: take the 11 white tablets first, followed by the 10 pink tablets.

After finishing all 21 tablets, take a 7-day tablet-free break.

Begin the next pack on the 8th day, regardless of whether menstrual bleeding has stopped.

If menstruation is still present, initiate treatment on the 5th day of the menstrual cycle.

In patients with amenorrhea or very infrequent menstruation, and in postmenopausal women, start treatment at any time after excluding pregnancy.

For the treatment of irregular menstrual cycles or amenorrhea, continue therapy for at least three months.

If a tablet is missed and less than 12 hours have passed, take it immediately and then the next tablet at the usual time.

If more than 12 hours have passed, skip the missed tablet and continue the regular schedule; use non-hormonal contraception for the next 7 days.

In case of breakthrough bleeding or spotting during the first few months of therapy, continue treatment as prescribed.

If irregular bleeding persists or begins after a period of regular cycles, conduct investigation to rule out organic pathology.

Adverse Reactions

From the organ of vision: visual disturbances, contact lens intolerance.

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 gastrointestinal tract: dyspepsia, bloating, nausea, vomiting, abdominal pain.

From the immune system: hypersensitivity reactions.

From metabolism: increase or decrease in body weight.

From the musculoskeletal system: muscle cramps.

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

From the CNS: headache, migraine, dizziness.

From the cardiovascular system: palpitations.

Contraindications

Pregnancy and 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; liver tumors currently or in history (benign or malignant); severe liver diseases; acute arterial thrombosis or thromboembolism (such as myocardial infarction, stroke); deep vein thrombosis in the acute stage, thromboembolism currently or in history; severe hypertriglyceridemia; hypersensitivity to the components; childhood and adolescence under 18 years of age.

With caution

Arterial hypertension, congenital hyperbilirubinemias (Gilbert, Dubin-Johnson and Rotor syndromes), cholestatic jaundice or cholestatic pruritus during pregnancy, endometriosis, uterine fibroids, diabetes mellitus, epilepsy, chorea minor, bronchial asthma, migraine, porphyria.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and during lactation (breastfeeding).

Use in Hepatic Impairment

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

Pediatric Use

Use is contraindicated in children and adolescents under 18 years of age.

Special Precautions

Not used for contraception.

If contraception is necessary, non-hormonal methods should be used (except for the calendar and temperature methods). If pregnancy is suspected, intake 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.

When prescribing HRT to women with risk factors for VTE, the risk-benefit ratio of treatment should be carefully weighed and discussed with the patient.

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

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.

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

During the use of sex steroids, which include HRT drugs, benign, and even more rarely, malignant liver tumors have been observed in rare cases. In some cases, these tumors led to life-threatening intra-abdominal bleeding. In case of 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 developing gallstone disease during treatment with estrogens.

Other conditions

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

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 pruritus, observed for the first time during pregnancy or previous treatment with sex steroid hormones, HRT should be discontinued 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 may affect peripheral insulin resistance and glucose tolerance, there is usually no need to change the treatment regimen for patients with diabetes during HRT. Nevertheless, women suffering from 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 discontinue 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 ultraviolet 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, parameters of carbohydrate metabolism, coagulation and fibrinolysis.

Drug Interactions

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

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 property is also assumed for oxcarbazepine, topiramate, felbamate and griseofulvin. Maximum enzyme induction is usually observed no earlier than after 2-3 weeks, but then it can persist for at least another 4 weeks after discontinuation of the drug.

In rare cases, during concomitant administration of certain antibiotics (for example, from the penicillin and tetracycline groups), a decrease in estradiol levels has been observed.

Substances that undergo significant 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, the requirement for oral hypoglycemic agents or insulin may change in individual cases.

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

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.