Climodien^® (Tablets) Instructions for Use

Marketing Authorization Holder

Bayer Schering Pharma AG (Germany)

Manufactured By

Schering, GmbH & Co. Produktions KG (Germany)

ATC Code

G03FA (Progestogens and estrogens (fixed combinations))

Active Substances

Estradiol valerate (Rec.INN registered by WHO)

Dienogest (Rec.INN registered by WHO)

Dosage Form

Climodien®

Sugar-coated tablets, 2 mg+2 mg: 28 pcs.

Dosage Form, Packaging, and Composition

Excipients: lactose monohydrate, potato starch, gelatin, magnesium stearate, magnesium hydrosilicate (talc).

Shell composition: sucrose, liquid dextrose, calcium carbonate, povidone K25, macrogol 35000, titanium dioxide (E171), iron (III) oxide (E172), carnauba wax.

28 pcs. – calendar blister packs (1) – cardboard boxes.

Clinical-Pharmacological Group

Anticlimacteric drug

Pharmacotherapeutic Group

Antimenopausal agent (estrogen + progestogen)

Pharmacological Action

Climodien^® contains Estradiol valerate – an estrogen that is converted in the woman’s body into natural 17β-estradiol, and Dienogest – a highly effective synthetic progestogen, the only derivative of norethisterone with a pronounced antiandrogenic effect.

Estradiol valerate replenishes the estrogen deficiency in the female body after menopause and provides effective treatment of psychoemotional and autonomic menopausal symptoms such as hot flashes, increased sweating, sleep disturbances, increased nervous excitability, dizziness, headache; involutional processes of the skin and mucous membranes, especially the mucous membranes of the urogenital system, manifested as urinary incontinence, vaginal dryness and irritation, pain during intercourse.

Dienogest prevents the development of endometrial hyperplasia, leads to its atrophy, promotes reduction, and subsequently cessation of bloody vaginal discharge – amenorrhea develops in 67% of women after 3 months and in 85% of women after 12 months of therapy.

The use of Climodien^® leads to a decrease in the level of total cholesterol, low-density lipoprotein cholesterol (LDL) and an increase in high-density lipoprotein cholesterol (HDL), resulting in a significant increase in the HDL/LDL ratio.

There is evidence that estrogens have a direct effect on blood vessels. Clinical studies have shown that the use of Climodien^® increases markers in the urine that reflect the presence of a vasodilatory effect. A direct comparison of Climodien^® with estradiol valerate monotherapy showed that Dienogest does not reduce this effect. Estradiol prevents estrogen deficiency-induced bone loss in the postmenopausal period. This is mainly due to the suppression of osteoclast function and a shift in the bone remodeling process towards bone formation. This effect of Climodien^® is confirmed by measuring the levels of specific bone markers such as alkaline phosphatase and the cross-linked collagen groups pyridinoline and deoxypyridinoline.

In a clinical study in women suffering from insomnia associated with postmenopausal syndrome, Climodien^® improved subjective sleep quality.

Pharmacokinetics

Estradiol valerate

Absorption

After oral administration, Estradiol valerate is absorbed rapidly and completely. During absorption and the first pass, the steroid ester is cleaved into estradiol and valeric acid. Subsequently, a significant amount of estradiol continues to be metabolized (in particular, to estrone, estriol, and estrone sulfate). Only about 3% of estradiol becomes bioavailable after oral administration of estradiol valerate. Food intake does not affect the bioavailability of estradiol.

Within 60 minutes after taking the tablet, the serum estradiol level decreases rapidly and reaches an average concentration of about 18 pg/ml. Then, the serum estradiol level slowly increases to a peak concentration of about 30 pg/ml – approximately 8 hours after taking the tablet.

Distribution

When 2 mg of estradiol valerate is administered, a high plasma level of estradiol is achieved within 30-60 minutes. The peak serum concentration is reached after 2-10 hours, with an estrone/estradiol ratio of 4:1.

Estradiol binds to albumin and sex hormone-binding globulin (SHBG). The free fraction of estradiol in serum is approximately 1-1.5%, and the fraction bound to SHBG is within 30-40%.

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

Metabolism

After cleavage of the ester from exogenous estradiol valerate, the drug’s metabolism follows the pathway of biotransformation of endogenous estradiol. Estradiol is mainly metabolized by the liver, partially by the intestine, kidneys, skeletal muscles, and target organs. This process involves the formation of estrone, estriol, catecholestrogens, as well as sulfate and glucuronide conjugates of the listed substances; all of them have much lower estrogenic activity than estradiol itself, or are completely inactive.

Elimination

Within 24 hours after oral administration of a single dose of estradiol valerate, the serum estradiol level decreases to about 10 pg/ml. The total serum clearance of estradiol after a single intravenous administration varies between 10-30 ml/min/kg. A certain part of estradiol is excreted with bile and undergoes enterohepatic recirculation. Ultimately, estradiol metabolites are excreted by the kidneys in the form of sulfates and glucuronides.

Steady-state concentration

Serum estradiol levels after repeated administration are 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 is approximately 7 times, and the concentration of estrone sulfate is approximately 150 times higher than the concentration of estradiol. After discontinuation of Climodien^®, estradiol and estrone levels return to baseline within two to three days.

Dienogest

Absorption

When taken orally, Dienogest is rapidly and almost completely absorbed. The peak serum concentration of dienogest is reached by the first hour after a single dose and is approximately 54 pg/ml. The absolute bioavailability after oral administration is about 90%.

Distribution

Dienogest binds to serum albumin and does not bind to SHBG or corticosteroid-binding globulin (CBG). Approximately 10% of the total amount of the steroid is in the free state, 90% is non-specifically bound to albumin.

Metabolism

Dienogest is completely metabolized primarily by hydroxylation, as well as hydrogenation, conjugation, and aromatization to form endocrinologically inactive metabolites. The metabolic clearance rate from serum is about 0.85 ml/min/kg.

Elimination

The serum level of dienogest decreases in two phases. The terminal phase is characterized by a half-life of about 11 hours. Dienogest is not excreted unchanged. Its metabolites are excreted mainly by the kidneys. In postmenopausal women, the total clearance after oral administration of Climodien^® is 3.2 l/hour.

Steady-state concentration

The pharmacokinetics of dienogest are not influenced by SHBG levels. With daily intake of the drug, the serum level of dienogest increases approximately 1.3 times and reaches a steady-state concentration during the first half of the application cycle.

Indications

• Hormone replacement therapy (HRT) for symptoms of estrogen deficiency in women (not earlier than one year after the onset of menopause).

ICD codes

Dosage Regimen

Women starting HRT for the first time or switching from another drug for continuous HRT can start it at any time provided that at least one year has passed since the onset of menopause.

When switching to Climodien^® from another continuous or cyclic hormone replacement therapy, it is necessary to finish the current cycle of that drug.

Each package is designed for 28 days of use. Treatment is carried out in a continuous regimen, starting the next pack immediately after finishing the previous one. Take one tablet daily, preferably at the same time, with a small amount of liquid.

If a woman forgets to take a tablet, she should take it as soon as possible. If more than 24 hours have passed, there is no need to take an additional tablet. If several tablets are missed, spotting/vaginal bleeding may occur.

Hormone replacement therapy with Climodien^® promotes the cessation of cyclic bleeding; however, the patient should be warned that during the first few months of use, acyclic spotting/vaginal bleeding may occur, the severity of which may subsequently decrease, up to their complete cessation.

Adverse Reactions

In multicenter studies involving 1834 women who received Climodien^® for at least 6 cycles, the following adverse events were most common: breakthrough bleeding (24%) and breast tenderness/pain (13%).

The table is based on the classification of organ systems according to MedDRA (Medical Dictionary for Regulatory Activities).

In 7 clinical trials of Climodien^® involving 1834 women, the following adverse events were registered, the connection of which with the drug was assessed as at least possible.

The most appropriate medical terms (MedDRA version 8.0) are listed. Synonyms or similar conditions are not listed but should also be taken into account.

In addition to the situations discussed in the “Special Precautions” section, the following adverse events were noted in isolated cases during clinical trials of oral HRT drugs: fungal infections, increased appetite, dyspepsia, palpitations, visual disturbances, depression, changes in plasma liver enzyme levels, increase in the size of uterine fibroids.

In very rare cases, conditions such as erythema nodosum, erythema multiforme, chloasma, hemorrhagic dermatitis (vascular purpura) have been reported in women taking HRT.

Exogenous estrogens may cause or exacerbate symptoms of angioedema in women with hereditary angioedema (see “Special Precautions” section).

Contraindications

Hormone replacement therapy should not be used in the presence of any of the conditions/diseases listed below. If any of these conditions/diseases develops for the first time while taking Climodien^®, the drug should be discontinued immediately.

• Pregnancy and lactation;
• Vaginal bleeding of unknown origin;
• Established or suspected diagnosis of breast cancer;
• Presence or suspicion of hormone-dependent precancerous conditions/diseases or malignant tumors;
• Current or history of liver tumors (benign or malignant);
• Severe liver diseases;
• Acute arterial thrombosis or thromboembolism (e.g., myocardial infarction, stroke);
• Current deep vein thrombosis, thromboembolism or reliable information about these conditions in the past;
• Severe hypertriglyceridemia;
• Established hypersensitivity to any component of Climodien^®.

With caution

Climodien^® should be prescribed with caution for the following diseases and conditions.

• Risk factors for thrombosis (including severe obesity);
• Arterial hypertension;
• Diseases of the liver or gallbladder, including congenital hyperbilirubinemias (Gilbert’s, Dubin-Johnson and Rotor syndromes), jaundice and/or cholestatic pruritus during pregnancy or previous use of sex hormones;
• Endometriosis and uterine fibroids (including history);
• Moderate hypertriglyceridemia;
• Diabetes mellitus.

Women with epilepsy, benign breast tumors, bronchial asthma, migraine, porphyria, otosclerosis, systemic lupus erythematosus, chorea minor should be under close medical supervision during HRT. These conditions/diseases may occur or worsen during HRT, although their relationship with hormone replacement therapy has not been proven.

Use in Pregnancy and Lactation

HRT is not prescribed during pregnancy or breastfeeding. A small amount of sex hormones may be excreted in breast milk.

If pregnancy is suspected, the drug should be discontinued until pregnancy is ruled out.

Large-scale epidemiological studies have not revealed an increased risk of congenital defects in children born to women who took steroid hormones for contraception or HRT before pregnancy. No teratogenic effect of hormones was found when they were accidentally taken in early pregnancy.

Use in Hepatic Impairment

Prohibited for use in severe liver diseases, current or history of liver tumors (benign or malignant).

With caution: diseases of the liver or gallbladder, including congenital hyperbilirubinemias (Gilbert’s, Dubin-Johnson and Rotor syndromes), jaundice.

Special Precautions

Climodien^® is not used for contraception.

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

In the presence or worsening of any of the conditions, diseases or risk factors listed below, the risk-benefit ratio of treatment should be assessed individually for each woman before starting or continuing HRT.

HRT should be discontinued immediately if the following disorders occur.

• The first occurrence of migraine or any unusually frequent or unusually severe headaches, sudden visual or hearing impairment, or other symptoms indicating possible cerebrovascular occlusion;
• Development of jaundice, including recurrence of cholestatic jaundice or cholestatic pruritus, which were first observed during pregnancy or previous treatment with sex steroid hormones;
• Appearance of symptoms of thrombotic disorders or suspicion of their occurrence. If health status changes and/or risk factors appear (occurrence of new disorders, worsening of existing ones), a reassessment of the risk/benefit ratio of the therapy for the patient should be performed, including the possibility of discontinuing treatment.

Venous thromboembolism

A number of controlled randomized, as well as epidemiological studies have revealed an increased relative risk of developing 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 (VTE in close relatives at a relatively young age may indicate 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 discontinuing HRT should be considered.

Arterial thromboembolism

In large-scale clinical studies using conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA), a small increase in the risk of coronary heart disease (CHD) was detected in the first year of use, with no subsequent positive effect on CHD.

In one large-scale clinical study using CEE alone, a potential reduction in the incidence of CHD was found in a subgroup of women aged 50-59 years – in the absence of an overall reduction in the incidence of CHD among all women participating in the study. As a secondary outcome, two large-scale clinical studies using CEE as monotherapy or in combination with MPA revealed a 30-40% increased risk of stroke. It is unknown whether these data can be extrapolated to other HRT drugs, including non-oral ones.

Gallbladder diseases

It is known that estrogens increase the lithogenicity of bile. Some women are predisposed to the development of cholelithiasis when treated with estrogens.

Dementia

Clinical trials with drugs containing conjugated equine estrogens have provided limited data indicating that hormone therapy initiated for the first time in women aged 65 years or older may increase the risk of probable dementia. At the same time, the risk of developing dementia may be reduced if treatment is started in early postmenopause, as observed in other studies. It is unknown whether these data can be extrapolated to other HRT drugs.

Endometrial cancer

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

Breast cancer

According to clinical trial data and results from observational studies, an increased relative risk of developing breast cancer was found in women using HRT for several years compared to women of the same age who never received it. This may be associated with earlier diagnosis, acceleration of the growth of an existing tumor during HRT, or a combination of both factors.

Assumptions regarding the increased risk of breast cancer are based on the results of more than 50 epidemiological studies (risk varies from 1 to 2). In two large-scale randomized trials with monotherapy of conjugated equine estrogens (CEE) or their continuous combination with medroxyprogesterone acetate (MPA), the calculated risk rates were 0.77 (95% confidence interval; 0.59 – 1.01) or 1.24 (95% confidence interval: 1.01 – 1.54) after 6 years of HRT use. It is unknown whether this increased risk also applies to other HRT drugs.

The relative risk increases with the duration of treatment, but may be absent or reduced with estrogen monotherapy.

A comparable increase in the risk of breast cancer is also observed 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 within a few years after discontinuation of HRT.

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

Data on the spread of cancer beyond the breast remain controversial.

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

Liver tumor

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. When conducting a differential diagnosis in case of pain in the upper abdomen, liver enlargement, or signs of intra-abdominal bleeding, a liver tumor should be excluded.

Other conditions

The relationship between HRT and the development of clinically significant arterial hypertension has not been established. A small increase in blood pressure has been described in women taking 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 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 and/or jaundice develops, HRT should be discontinued.

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 in patients with diabetes mellitus during HRT. Nevertheless, women with diabetes mellitus should be under medical supervision during HRT.

Some patients may develop undesirable effects of estrogen exposure during HRT, such as abnormal uterine bleeding. Frequent or persistent abnormal uterine bleeding during treatment is an indication for endometrial assessment.

Under the influence of estrogens, uterine fibroids may increase in size. In such cases, 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 therapy.

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.

Exogenous estrogens may cause or exacerbate symptoms of angioedema in women with hereditary angioedema.

Medical examination and counseling

Before starting or resuming HRT, a woman is recommended to undergo a thorough general medical and gynecological examination, including examination of the mammary glands, abdominal and pelvic organs, cytological examination of a cervical smear (Pap test), blood pressure measurement, and exclusion of pregnancy. In addition, blood clotting disorders should be excluded. The scope of additional examinations and the frequency of follow-up visits is determined individually.

Effect on ability to drive vehicles and operate complex machinery

No effect observed.

Overdose

Acute toxicity studies have not revealed a risk of acute side effects in case of unintentional intake of Climodien^® in an amount significantly exceeding the daily therapeutic dose.

In some women, overdose may cause nausea, vomiting, acyclic vaginal bleeding.

There is no specific antidote.

Drug Interactions

Before starting HRT, it is necessary to discontinue the use of hormonal contraceptives. If necessary, the patient should be recommended a non-hormonal method of contraception.

Drug interactions

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 effectiveness. This effect has been established for hydantoin, phenytoin, barbiturates, primidone, carbamazepine, and rifampicin. Oxcarbazepine, felbamate, topiramate, and griseofulvin are also presumed to have this ability. Usually, the maximum increase in enzyme activity is observed no earlier than 2-3 weeks after starting these drugs and may persist for at least 4 weeks after their discontinuation.

In rare cases, a decrease in estradiol levels is observed with the simultaneous administration of certain antibiotics (e.g., penicillins and tetracyclines). Substances that undergo significant conjugation (e.g., paracetamol) may increase the bioavailability of estradiol through competitive inhibition of the conjugation system during intestinal absorption.

In individual cases, the requirement for oral hypoglycemic agents and insulin may change due to the effect of HRT on glucose tolerance.

In vitro studies have demonstrated that Dienogest does not inhibit cytochrome P-450 isoenzymes at significant concentrations, which is proven for the inhibition of CYP3A4. Thus, there is no likelihood of drug-drug interaction at this level.

Interaction with alcohol

A single consumption of a significant amount of alcohol by women receiving HRT may lead to an increase in the level of estradiol in the circulating blood.

Effect on laboratory tests

Intake of sex steroids may affect biochemical parameters of liver, thyroid, adrenal and kidney function, as well as levels of plasma transport proteins such as corticosteroid-binding globulin (CBG) and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and hemostasis (coagulation and fibrinolysis).

Storage Conditions

The drug should be stored at a temperature not exceeding 25°C (77°F). Keep out of reach of children!

Shelf Life

Shelf life – 3 years.

Do not use after the expiration date!

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.