Cabergoline: 30 years of experience and trust

Hyperprolactinemia is the most common endocrine pathology of the hypothalamic-pituitary system. It occurs more often among women than among men. Clinical symptoms of hyperprolactinemia are: menstrual irregularities up to amenorrhea, infertility, galactorrhea in women, decreased libido, impaired potency in men. In 60% of cases, hyperprolactinemia is caused by a prolactin-secreting pituitary adenoma (prolactinoma) [4]. Common causes include medications that interfere with the prolactin-inhibitory effect of dopamine, primary hypothyroidism, hypothalamic or pituitary tumors that cause compression of the pituitary gland, as well as idiopathic hyperprolactinemia. Since the main role in the pathogenesis of hyperprolactinemia is played by disruption of dopaminergic regulation, since the 70s of the last century, medications with dopaminergic effects have been used as prolactin-inhibiting drugs. Stimulation of D2 receptors localized on lactotrophs inhibits the activity of adenylate cyclase, which in turn reduces the intracellular content of cAMP, suppressing the transcription of the corresponding gene and the secretion of prolactin [2].

To treat hyperprolactinemic conditions, doctors have short- and long-acting dopamine agonists in their arsenal. Bromocriptine is the first semi-synthetic ergot alkaloid, which has found widespread use in clinical practice since 1972. However, the non-selectivity of the drug has led to the development of a fairly wide range of side effects. Cabergoline, registered in 1982, is more effective and has fewer side effects due to its increased affinity for D2 receptors and prolonged elimination from the body [15]. In Russia, this drug has been used for more than 15 years.

According to international clinical guidelines for the diagnosis and treatment of hyperprolactinemia, cabergoline is recognized as the most effective drug from the group of dopamine agonists and is recommended as first-line therapy [24]. This statement was based on a significant amount of data obtained over more than 30 years of use of the drug. It is necessary to note the versatility of cabergoline, the dopaminergic effects of which are used not only in the treatment of patients with hyperprolactinemia, but also in Parkinson's disease and parkinsonism. Moreover, a number of recent publications are devoted to the discovery of new potential pharmacological targets for cabergoline. It has been shown that during the treatment of patients with hyperprolactinemia, there is a significant improvement in a number of metabolic parameters, namely: a decrease in atherogenic indicators of the lipid spectrum, insulin resistance index, body weight, homocysteine level, as well as a decrease in the intima-media complex of the carotid arteries, regardless of the rate and severity of the decrease prolactin level [13, 18, 19]. In this connection, studying the mechanism of the antiatherogenic effect of cabergoline seems very interesting in the future. Nevertheless, due to the widespread use of the drug in women with hyperprolactinemic infertility, the most pressing issue remains the safety of cabergoline during pregnancy [1]. Over the past decade, a significant amount of data has accumulated on the use of cabergoline in early gestation.

The first experience of using cabergoline during pregnancy belongs to Italian scientists. In 1989, S. Ferrari et al. described 17 cases of pregnancies that resulted in the birth of healthy children.

One of the largest studies on this problem [30] was published jointly by Italian and English scientists in 1996. The study involved 206 women who followed 204 pregnancies between 1987 and 1994. The dose of cabergoline ranged from 0.25 mg to 4 mg per week, the period of taking the drug before conception also varied greatly - on average from 5 to 71 weeks. Early pregnancy losses were 12%; in 1 case the cause of termination was an ectopic pregnancy. In 3 patients, abortions were performed for medical reasons in the period from the 19th to the 22nd week due to fetal developmental anomalies (Down syndrome in a 42-year-old patient, hydrocephalus, brain atrophy). Premature birth was observed in 17 women; among all newborns, major malformations were noted only in 2 (3%) children. In the postpartum period, 107 children were observed; the physical and mental development of all newborns corresponded to age standards. A study by E. Robert et al. [30] was the first reliable evidence of the safety of cabergoline to initiate pregnancy in patients with hyperprolactinemia of various origins. The authors showed that the rate of miscarriage and the incidence of fetal malformations were comparable to those for European countries and did not correlate with the period of drug use or its dose.

Subsequently, in 1997, E. Ciccarelli et al. [12] presented data on the development of pregnancies in 9 patients treated with cabergoline for a duration of 1 to 37 months. Spontaneous termination of pregnancy was observed in one of the patients; data on the development of congenital anomalies were not provided.

In 1999, J. Velhelst et al. [35], during a comparative study of the effectiveness and safety of bromocriptine and cabergoline, observed the development of pregnancies in 27 patients receiving cabergoline, 25 of which resulted in the birth of healthy children. One of the patients had a spontaneous abortion; in another case, the pregnancy was terminated at the woman’s request. In the same year, data were published on the initiation of 6 pregnancies in patients who were first prescribed cabergoline, one of which ended in spontaneous abortion, the rest in the birth of healthy children [11].

In 2002, E. Ricci et al. [29] analyzed 61 pregnancies in 50 patients from 1990 to 2001. The treatment period before pregnancy was detected averaged 42.5 weeks (range 1 to 236), the average dose of cabergoline was 1.1 mg per week. The frequency of spontaneous abortions was 9.8%, which, as the authors of the study indicate, was comparable to similar indicators both for the region in which the patients lived - 8.2%, and for the Italian population as a whole, where the frequency of spontaneous abortions during the period from 1990 to 1995 ranged from 8 to 10 cases per 100 pregnancies. The rate of medical abortions in the study was 8.2%, one of which was performed due to suspected hydatidiform mole, in other cases abortions were performed according to the women's wishes. Among 49 newborns, one was diagnosed with trisomy 18; the mother took the drug for 76 weeks before conception. After giving birth, the patient continued taking cabergoline, and the subsequent pregnancy resulted in the birth of a healthy child. Premature births among pregnant women were observed in 8.6% of cases, the body weight of newborns varied between 1510-4230 g, 6 children had a body weight of less than 2500 g.

The results of the largest and most long-term study of the outcomes of pregnancies initiated by cabergoline were published by A. Colao et al. [14] in 2008. The group also included patients who participated in the study by E. Robert et al. [thirty]. The authors analyzed 329 pregnancies that occurred less than 6 weeks after discontinuation of cabergoline or while taking it. In 92 cases, an analysis was made of the duration of the effect of cabergoline on the fetus, which was less than 1 month in approximately 1/3 of the cases, 1-2 months in 47%, more than 2 months in less than 15%. Among the 329 pregnancies with known outcomes, 258 (78%) resulted in birth and 71 (22%) resulted in abortion. Of the 71 reported abortions, 31 (44%) were voluntary, 30 (42%) were spontaneous, 9 (13%) were for medical reasons, and the status of one abortion was unknown. Of the nine abortions performed for medical reasons, six were performed due to the presence of gross malformations of the fetus, including 3 Down syndrome, deformity of the lower extremities, hydrocephalus, and congenital absence of abdominal muscles syndrome. The incidence of fetal anomalies in the study was 6.6%. Among 258 births, 250 (97%) resulted in live births, in 4 (2%) cases the children were stillborn, and in 4 (2%) birth observations the status of the newborns was unknown. Of the 250 births that resulted in the birth of healthy children, 193 (77%) were considered as timely, 45 (18%) as premature, and in 12% of cases there was no information about the birth. The birth weight of 17 of 258 newborns was less than 2500 g, 78% of children had normal body weight. The authors of this study emphasized that the frequency of spontaneous abortions after the use of cabergoline in the treatment of hyperprolactinemia and initiation of pregnancy during therapy not only did not exceed the incidence of this outcome for the population of the USA and Europe, but was also lower - 9.8% compared to 11 -15% on the American continent and 11% for the European population. There was no increased risk of low and extremely low birth weight infants.

In 2010, 3 studies were published on this problem. Thus, M. Ono et al. [27] observed 85 women with macroprolactinomas (29) and microprolactinomas (56) who received high doses of cabergoline to overcome hyperprolactinemic infertility. This group included 31 patients with resistance to bromocriptine, 32 with intolerance to this drug, and 22 who had not previously been treated. The average dose of the drug was about 3.5 mg per week. Among 93 pregnancies, one ended in spontaneous abortion, in another case a medical abortion was performed at the request of the patient, 7 pregnancies continued to develop at the end of the study. Among 84 newborns, the body weight of 74 children was more than 2500 g, 9 (10.8%) children had low body weight. As the authors note, in Japan, where the study was conducted, the incidence of low birth weight babies is 10.6%. Preterm birth in patients was observed only in one case; the child was born at the 36th week of gestation. None of the children had any developmental defects; subsequently, all of them were under the supervision of a pediatrician for a maximum of 15 years; no retardation in linear growth or mental development was detected.

In a study by M. Lebbe et al. [21] presented the results of the outcomes of 100 pregnancies between 1997 and 2009 in 72 women with hyperprolactinemia. Almost all patients stopped taking cabergoline immediately after establishing the fact of pregnancy, but 8 women took the drug until the 10-12th week, 4 - until 15-22 weeks, 1 patient with macroprolactinoma - throughout the entire gestation period at a dose of 1 mg per week. This study included for the first time patients who became pregnant after in vitro fertilization (20% of all pregnancies). In 16 cases, pregnancies were interrupted: 10 women had spontaneous abortions in the period from the 5th to 16th week, 2 had abortions at the request of the woman, and 2 had removal of an ectopic pregnancy. However, the authors emphasize that the likelihood of miscarriage did not depend on the dose of cabergoline taken at the time of conception, or on the period of drug withdrawal during pregnancy or the cumulative dose of fetal exposure. At a later date, in the period from the 17th to the 20th week of gestation, three patients underwent termination of pregnancy for medical reasons. The majority of newborns (77%) had normal body weight; congenital defects were observed in 3 (3.4%) infants. The dose of cabergoline during pregnancy ranged from 0.5 mg to 6 mg. Upon further observation of the children, no lag in psychomotor and physical development was noted.

One of the largest recent studies of the course of cabergoline-induced pregnancies was the work of G. Stalldecker et al. [34], published in 2010. Researchers from Argentina analyzed the course and outcomes of 103 pregnancies in 90 patients with hyperprolactinemia. All women took cabergoline at the time of conception, the period of taking the drug ranged from 1 to 120 months, during gestation - from 3 to 25 weeks. The frequency of spontaneous abortions was 7.2%, premature births were observed in 8 cases, the frequency of developmental anomalies among newborns was 3.6%. Researchers traced the further fate of the children. Thus, among 61 children, 4 had neurological disorders. The authors indicate that the results obtained in the study do not exceed the incidence of these disorders in the general population.

The modern concept of managing pregnant women with prolactinomas involves discontinuing dopamine agonists immediately after pregnancy has been established [3, 9, 23, 24, 28]. Of course, in the presence of microprolactinoma while taking cabergoline in early pregnancy, the most important task is to minimize the effect of drug therapy on the fetus to avoid the development of adverse events. The situation is more complicated in the event of pregnancy in patients with macroprolactinoma. Recent studies [21, 25] have shown that the risk of symptomatic growth of macroprolactinoma during pregnancy increases significantly, reaching 27.9-47%. Resumption or worsening of symptoms forces the endocrinologist to continue prescribing dopamine agonists throughout the entire gestation period. Thus, J. Jones et al. [21] described the initiation and prolongation of pregnancy against the background of constant intake of cabergoline in a patient with macroprolactinoma and a high risk of damage to the optic chiasm. The dose of the drug varied from 0.5 to 2 mg per week. The pregnancy proceeded without complications, no visual field abnormalities were observed, and according to MRI results at the 29th week, positive dynamics were noted in the form of a decrease in the size of the adenoma. At 38 weeks of gestation, a healthy boy was born by caesarean section.

One of the most interesting cases was described by A. Banerje et al. [8]. A patient with a macroadenoma and bromocriptine intolerance was switched to cabergoline therapy at a dose of 0.5 mg 2 times a week. Pregnancy occurred 2 months after changing therapy. At the 6th week of gestation, the drug was discontinued, however, given the increase in clinical symptoms of significant tumor growth in the form of bitemporal hemianopsia and increased headaches, at the 18th week therapy was resumed with a gradual increase in the dose to 3 mg per week. Soon after reaching the maximum dose, the patient's condition improved, and MRI data confirmed the absence of compression of the chiasmal chiasm by the tumor. Unfortunately, the pregnancy was terminated at 34 weeks due to the development of preeclampsia, which resulted in placental abruption and intrauterine fetal death. Upon further examination, the patient was diagnosed with a mutation in one of the factors of the hemostatic system. It is unique that after 4 months, against the background of normalization of prolactin levels and a significant reduction in the size of the macroadenoma when taking 4.5 mg of cabergoline per week, the patient became pregnant again, which resulted in the birth of a healthy girl. Subsequently, this patient had two more successful pregnancies, during which she received cabergoline at a dose of 5.25 mg per week.

The literature provides data on better tolerability of cabergoline compared to bromocriptine in pregnant patients. Thus, G. Forsbach-Sánchez et al. [17] described 2 clinical cases of management of patients with macroprolactinomas during pregnancy, during which the increase in clinical symptoms of tumor growth required the resumption of dopamine agonist therapy. The patients were prescribed bromocriptine, but soon both women began to receive cabergoline due to intolerance to the previous drug. The pregnancies ended in the birth of healthy children. The experience of successful pregnancy in a patient with macroprolactinoma on the background of continuous intake of cabergoline at a dose of 0.5 mg per week was also described by Pakistani researchers [31]. The absence of the teratogenic effect of cabergoline was also shown in the works of R. de Turris et al. [16], J. Sharma et al. [32]. One clinical case indicates a favorable pregnancy outcome in a patient with macroprolactinoma when taking bromocriptine and cabergoline together [22].

Thus, to date, a significant amount of data has accumulated on the use of cabergoline during pregnancy. The frequency of spontaneous abortions among patients taking cabergoline during pregnancy is comparable to the general population - 12, 9.8, 9 and 7.2% in the largest studies and 5 cases among more than 60 pregnancies described as single clinical observations. The average frequency of spontaneous abortions in the population is about 10.9% [26], in Russia this figure is 10.4% [5], in Europe - 11% [26]. It is necessary to take into account that a slight excess in the frequency of spontaneous abortions in the study by E. Zhukova et al. [38] should not be fully associated with taking the drug during gestation, due to the fact that pregnant women with hyperprolactinemia syndrome are at risk of developing chronic placental insufficiency.

Currently, the outcomes of more than 600 births in patients taking cabergoline during pregnancy are known, among them, developmental anomalies in children were observed in 3.3% [25]. The population frequency of malformations averages from 3 to 7%, and among stillbirths reaches 11-18% [6], in the USA - about 3.0% [10], in Europe - 2.2% [36], in Russia according to the Federal Statistics Service for 2011 - 2.9% [37]. Thus, according to researchers and statistical data, taking cabergoline during pregnancy does not lead to an increased risk of developing fetal abnormalities.

In women treated with cabergoline, there was no increased risk of having low birth weight babies (less than 2500 g). In large studies, the incidence of low birth weight babies varied from 6 to 8%, which corresponds to international data for the normal population; in the USA this figure is about 7%, in North America and Europe - 4-8% [14], in Russia - up to 6 % [7].

The incidence of preterm birth in various studies ranged from 8.8 to 18%, when converted to the total number of pregnancies - 12.5% [25], which is also comparable to rates in the USA - 12-13% and Europe - 5-9% [ 33].

Of course, the follow-up period for children born to mothers who received cabergoline during pregnancy is quite short, and further research in this area is needed to evaluate the long-term results of therapy. However, the results of studies by G. Stalldecker et al. [34], A. Colao et al. [14], in which the maximum period of observation of children was 16 years and did not reveal an increased risk of developmental delays or neurological disorders, make it possible to judge the safety of the drug in the long term.

Kabergolin

Before prescribing cabergoline for the treatment of disorders associated with hyperprolactinemia, it is necessary to conduct a complete examination of the pituitary gland. In addition, the state of the cardiovascular system should be assessed, including echocardiography, in order to identify asymptomatic dysfunctions of the valve apparatus.

As with other ergot derivatives, pleural effusion/pleural fibrosis and valvulopathy have been observed in patients following long-term use of cabergoline. In some cases, patients had received prior therapy with ergotonine dopamine agonists. Therefore, cabergoline should not be used in patients with signs and/or clinical symptoms of cardiac or respiratory dysfunction associated with fibrotic changes or a history of such conditions. The drug should be discontinued if signs of the appearance or worsening of blood regurgitation, narrowing of the lumen of the valves or thickening of the valve leaflets are detected (see section “Contraindications”). It has been established that the erythrocyte sedimentation rate increases with the development of pleural effusion or fibrosis. If an unexplained increase in erythrocyte sedimentation rate is detected, a chest x-ray is recommended. A study of the concentration of creatinine in the blood plasma and an assessment of renal function can also help in making a diagnosis. Patients with pleural effusion/pleural fibrosis or valvulopathy experienced improvement in symptoms after discontinuation of cabergoline. It is unknown whether cabergoline can worsen the condition of patients with signs of blood regurgitation. Cabergoline should not be used if fibrous lesions of the heart valve apparatus are detected (see section “Contraindications”). Fibrotic disorders can develop asymptomatically. In this regard, the condition of patients receiving long-term therapy with cabergoline should be regularly monitored and special attention should be paid to the following symptoms:

- pleuropulmonary disorders: such as shortness of breath, difficulty breathing, persistent cough or chest pain;

- renal failure or obstruction of the vessels of the ureters or abdominal organs, which may be accompanied by pain in the side or lumbar region and swelling of the lower extremities, any swelling or tenderness when touched in the abdomen, which may indicate the development of retroperitoneal fibrosis;

— pericardial fibrosis and fibrosis of the heart valve leaflets often manifest as heart failure. In this regard, it is necessary to exclude fibrosis of the heart valves (constrictive pericarditis) when symptoms of heart failure appear.

The patient's condition should be regularly monitored for the development of fibrotic disorders. The first time EchoCG should be performed 3-6 months after the start of therapy. This study should then be carried out depending on the clinical assessment of the patient's condition, paying special attention to the symptoms described above, at least every 6-12 months of therapy.

The need for other monitoring methods (eg, physical examination, including cardiac auscultation, radiography, computed tomography) is assessed individually for each patient.

When increasing the dose, patients should be under medical supervision in order to establish the lowest effective dose that provides a therapeutic effect. After an effective dosage regimen has been selected, it is recommended to regularly (once a month) determine the concentration of prolactin in the blood plasma. Normalization of prolactin concentrations is usually observed within 2-4 weeks of treatment.

After discontinuation of the drug cabergoline, a relapse of hyperprolactinemia is usually observed, but some patients experience a persistent decrease in prolactin concentrations over several months. Most women maintain ovulatory cycles for at least 6 months. after discontinuation of the drug cabergoline.

Cabergoline restores ovulation and fertility in women with hyperprolactinemic hypogonadism. Since pregnancy may occur before menstruation returns, it is recommended that pregnancy tests be performed at least once every 4 weeks during the amenorrheic period, and after menstruation returns, whenever menstruation is more than 3 days late. Women wishing to avoid pregnancy should use barrier methods of contraception during treatment with cabergoline, as well as after discontinuation of the drug until anovulation recurs. Women who become pregnant should be under the supervision of a doctor to promptly identify symptoms of an enlarged pituitary gland, since during pregnancy it is possible that pre-existing pituitary tumors may increase in size.

Cabergoline should be prescribed in lower doses to patients with severe hepatic impairment (Child-Pugh class C) who are candidates for long-term therapy with the drug. With a single dose of 1 mg administered to such patients, an increase in AUC (area under the concentration-time curve) was observed compared with healthy volunteers and patients with less severe liver failure.

The use of cabergoline causes drowsiness. In patients with Parkinson's disease, the use of dopamine receptor agonists may cause sudden sleep onset. In such cases, it is recommended to reduce the dose of cabergoline or discontinue therapy.

No studies have been conducted on the use of the drug in elderly patients with disorders associated with hyperprolactinemia. The safety and effectiveness of the drug in children under 16 years of age have not been established.

Cabergoline, 0.5 mg, tablets, 2 pcs.

Before prescribing cabergoline for the treatment of disorders associated with hyperprolactinemia, it is necessary to conduct a complete examination of the pituitary gland.

In addition, the state of the cardiovascular system should be assessed, including echocardiography, in order to identify asymptomatic dysfunctions of the valve apparatus.

As with other ergot derivatives, pleural effusion/pleural fibrosis and valvulopathy have been observed in patients after long-term use of cabergoline. In some cases, patients had received prior therapy with ergotonine dopamine agonists. Therefore, cabergoline should not be used in patients with signs and/or clinical symptoms of cardiac or respiratory dysfunction associated with fibrotic changes or a history of such conditions. The drug should be discontinued if signs of the appearance or worsening of blood regurgitation, narrowing of the lumen of the valves or thickening of the valve leaflets are detected (see section “Contraindications”).

The erythrocyte sedimentation rate has been found to increase with the development of pleural effusion or fibrosis. If an unexplained increase in erythrocyte sedimentation rate is detected, a chest x-ray is recommended. A study of the concentration of creatinine in the blood plasma and an assessment of renal function can also help in making a diagnosis. Patients with pleural effusion/pleural fibrosis or valvulopathy experienced improvement in symptoms after discontinuation of cabergoline. It is unknown whether cabergoline can worsen the condition of patients with signs of blood regurgitation. Cabergoline should not be used if fibrous lesions of the heart valve apparatus are detected (see section “Contraindications”).

Fibrotic disorders can develop asymptomatically. In this regard, the condition of patients receiving long-term therapy with cabergoline should be regularly monitored and special attention should be paid to the following symptoms:

- pleuropulmonary disorders: such as shortness of breath, difficulty breathing, persistent cough or chest pain;

— pericardial fibrosis and fibrosis of the heart valve leaflets often manifest as heart failure. In this regard, it is necessary to exclude fibrosis of the heart valves (and constrictive pericarditis) when symptoms of heart failure appear.

The patient's condition should be regularly monitored for the development of fibrotic disorders. The first time EchoCG should be performed 3–6 months after the start of therapy. This study should then be carried out depending on the clinical assessment of the patient's condition, paying special attention to the symptoms described above, at least every 6-12 months of therapy.

The need for other monitoring methods (eg, physical examination, including cardiac auscultation, radiography, computed tomography) is assessed individually for each patient.

Cabergoline restores ovulation and fertility in women with hyperprolactinemic hypogonadism. Since pregnancy may occur before menstruation returns, it is recommended that pregnancy tests be performed at least once every 4 weeks during the amenorrheic period, and after menstruation returns, whenever menstruation is more than 3 days late. Women wishing to avoid pregnancy should use barrier methods of contraception during treatment with cabergoline, as well as after discontinuation of the drug until anovulation recurs. Women who become pregnant should be under medical supervision to promptly identify symptoms of an enlarged pituitary gland, since pre-existing pituitary tumors may increase in size during pregnancy.

Cabergoline should be prescribed in lower doses to patients with severe hepatic impairment (Child-Pugh class C) who are candidates for long-term therapy with the drug. When administered once to such patients, doses

mg there was an increase in AUC (area under the concentration-time curve) compared to healthy volunteers and patients with less severe hepatic impairment.

Impact on the ability to drive vehicles or operate machinery

Patients taking the drug cabergoline should refrain from driving vehicles and machinery and other potentially dangerous activities that require concentration and speed of psychomotor reactions.

Caberlin 0.5 mg tablets No. 2x1

Name

Caberlin tab 0.5 mg cont b/cell pack No. 2x1

Main active ingredient

Cabergoline

Release form

pills

Compound

One tablet contains: active ingredient: cabergoline – 0.5 mg; excipients: microcrystalline cellulose (Avicel PH 200), L-leucine.

Description

Tablets are white, round, flat-cylindrical, chamfered, with “SUN” engraving on one side and with a separating line on the other side.

Dosage

0.5 mg

Pharmacological properties

Pharmacodynamics

Cabergoline is a derivative of ergot alkaloids, a dopamine D2 receptor agonist. Stimulates dopamine D2 receptors, as a result of which it causes a pronounced and long-term inhibition of the secretion of the hormone of the anterior pituitary gland - prolactin. Cabergoline has low affinity for dopamine D1 receptors, α-1-, β-2 adrenergic receptors, 5-HT1- and 5HT2-serotonin receptors. Cabergoline has a therapeutic effect in hyperprolactinemia, reducing the severity of such manifestations as menstrual irregularities (oligomenorrhea, amenorrhea), infertility, galactorrhea, impotence, and decreased libido. Prevents and suppresses physiological lactation. The prolactin-lowering effect is dose-dependent both in terms of the severity and duration of action of cabergoline. Cabergoline has a selective effect and does not affect the basal secretion of other pituitary hormones, as well as cortisol.

Pharmacokinetics

After oral administration, cabergoline is rapidly absorbed from the gastrointestinal tract. Cmax in blood plasma is achieved after 0.5-4 hours. Food intake does not affect the absorption and distribution of cabergoline. A decrease in prolactin concentration is observed 3 hours after taking cabergoline and persists for 7-28 days in patients with hyperprolactinemia and 14-21 days in cases of suppressed postpartum lactation. The drug is intensively distributed in the body. Cabergoline is moderately bound (40% to 42%) to plasma proteins regardless of concentration. Concomitant use of drugs with high protein binding does not affect the content of cabergoline. Cabergoline is extensively metabolized. The main product of cabergoline metabolism identified in urine is 6-allyl-8?-carboxyergoline in concentrations up to 4–6% of the dose taken. The content of 3 additional metabolites in the urine does not exceed 3% of the dose taken. Metabolic products have a significantly lesser effect in suppressing prolactin secretion compared to cabergoline. The participation of cytochrome P450 in metabolism is minimal. T?, estimated by the rate of excretion in urine, is 79-115 hours in patients with hyperprolactinemia.

Indications for use

Inhibition/suppression of physiological lactation Inhibition of physiological postpartum lactation immediately after childbirth or to suppress lactation established in the following cases: - after childbirth, if the mother has decided not to breastfeed, or when breastfeeding is contraindicated for the mother or child for medical reasons; - after stillbirth or abortion. Treatment of hyperprolactinemic conditions Disorders associated with hyperprolactinemia, including amenorrhea, oligomenorrhea, anovulation and galactorrhea. Treatment of patients with prolactin-secreting pituitary adenomas (micro- and macroprolactinomas), idiopathic hyperprolactinemia or empty sella syndrome with concomitant hyperprolactinemia, which are the main pathological conditions causing the above-mentioned clinical manifestations.

Contraindications

Hypersensitivity to cabergoline, other ergot alkaloids, or to any component of the drug. A history of fibrotic disease of the lungs, pericardium and retroperitoneum. Liver failure and toxemia in pregnant women. Concomitant use of antipsychotic drugs. With long-term treatment: signs of damage to the heart valves are determined using echocardiography before treatment. Postpartum hypertension or uncontrolled arterial hypertension. Preeclampsia, eclampsia. History of psychosis or risk of developing postpartum psychosis.

Use during pregnancy and lactation

Pregnancy Adequate and well-controlled studies of the use of cabergoline in pregnant women have not been conducted. Animal studies have demonstrated no teratogenic effects, but decreased fertility and embryotoxicity associated with pharmacodynamic activity have been reported. Cases of major congenital malformations or premature termination of pregnancy have been reported following cabergoline therapy in pregnant women. The most common neonatal anomalies were musculoskeletal pathologies and cardiopulmonary anomalies. There are no data on perinatal disorders and on the subsequent development of infants after prenatal exposure to cabergoline. Available publications estimate the prevalence of major congenital malformations in the general population to be 6.9% or higher. The incidence of congenital anomalies varies among different populations. It is impossible to accurately determine whether there is an increased risk. Pregnancy should be ruled out before starting cabergoline and pregnancy should be avoided for at least one month after the end of therapy. Since cabergoline has a half-life of 79-115 hours in patients with hyperprolactinemia, once a regular ovulatory cycle has been established, women who wish to become pregnant should stop taking Cabergoline 0.5 one month before planned fertilization. This will prevent the possible effect of the drug on the fetus and does not prohibit the possibility of fertilization, since in some cases the ovulatory cycle persists for six months after discontinuation of the drug. If fertilization occurs during treatment, therapy should be discontinued once pregnancy is confirmed in order to limit the effect of the drug on the fetus. After discontinuation of cabergoline, contraception should be used for at least 4 weeks. Cabergoline restores ovulation and fertility in women with hyperprolactinemic hypogonadism: so that pregnancy may occur before the menstrual cycle is restored, it is recommended that a pregnancy test be performed during the amenorrheic period, after menstruation has resumed - whenever menstruation is delayed by more than three days. Women who do not wish to become pregnant are advised to use effective non-hormonal contraception during treatment and after discontinuation of cabergoline. Due to the long half-life and limited experience with the safety effects of cabergoline on the fetus, fertilization is recommended for women planning a pregnancy at least one month after stopping cabergoline. After pregnancy, women should be monitored for signs of pituitary enlargement, as existing pituitary tumors may grow during pregnancy. Breastfeeding Due to its ability to suppress lactation, Caberlin 0.5 should not be used by women with hyperprolactinemic disorders who are ready to breastfeed. Caberlin 0.5 and/or its metabolites were excreted into milk in a study in rats. There is no information available regarding excretion into human breast milk; however, women should be advised not to breastfeed if cabergoline does not suppress lactation.

Directions for use and doses

Caberlin 0.5 is intended for oral use. Since in clinical studies Caberlin 0.5 was used primarily with food, and thus the tolerability of this class of drugs when taken with food improves, the drug is recommended to be taken with food for all therapeutic indications. Inhibition/suppression of physiological lactation Caberlin 0.5 should be used during the first day after birth. The recommended therapeutic dose is 1 mg (2 tablets of 0.5 mg), taken once. To suppress lactation that has already been established, the recommended therapeutic dosage regimen is 0.25 mg (1/2 tablet of 0.5 mg) every 12 hours for 2 days (total dose - 1 mg). This dosing regimen is better tolerated by women who decide to suppress lactation than a single dose, and is accompanied by a lower incidence of adverse events, especially symptoms of arterial hypotension. Treatment of hyperprolactinemic conditions The recommended initial dose of Caberlin 0.5 is 0.5 mg once a week or 1/2 tablet of 0.5 mg 2 times a week (for example, on Monday and Thursday). The weekly dose should be increased gradually, preferably by 0.5 mg per week every month until optimal therapeutic efficacy is achieved. The usual therapeutic dose is 1 mg per week and can range from 0.25 to 2 mg per week. To treat patients with hyperprolactinemia, Caberlin 0.5 was used in doses of up to 4.5 mg per week. The maximum dose of the drug should not exceed 3 mg per day. The weekly dose of the drug can be taken at one time or divided into two or more doses per week, depending on the patient’s tolerability of the drug. If prescribed doses exceed 1 mg per week, it is recommended that the weekly dose be divided into several divided doses, since the tolerability of the drug at a dose exceeding 1 mg when taken as a single weekly dose has been assessed in only a few patients. When increasing the dose, the patient should be examined to determine the minimum dose of the drug that causes a therapeutic effect. Once an effective therapeutic dosage regimen has been selected, regular (monthly) determination of serum prolactin levels is recommended, since normalization of this level is usually observed within two to four weeks. After discontinuation of Caberlina 0.5, a relapse of hyperprolactinemia is usually observed. However, some patients experienced continued suppression of prolactin levels for several months. In 23 of 29 women in the follow-up group, ovulatory cycles lasted longer than 6 months after discontinuation of Caberlin 0.5. Elderly patients Experience with the drug in elderly patients is very limited due to the proposed indications for the use of the drug Caberlin 0.5. Available data indicate that there is no particular risk. Dose reduction or discontinuation of treatment The advisability of dose reduction or discontinuation of treatment should be considered if patients have: - drowsiness or cases of sudden falling asleep; - liver dysfunction.

Side effect

In general, adverse events depend on the dose of the drug. In patients with known intolerance to dopaminergic drugs, the likelihood of adverse events can be reduced by starting treatment with Caberlin 0.5 with lower doses, for example, 0.25 mg once a week, followed by a gradual increase until a therapeutic dose is reached. If persistent or severe side effects occur, a temporary dose reduction followed by a more gradual increase, for example, by 0.25 mg/week every 2 weeks, may improve tolerability. During treatment with Caberlin 0.5, the following adverse reactions were observed and reported with the following frequencies: very common > 1/10; hourly: > 1/100 and 1/1000 and 1/10000 and

Overdose

Symptoms of overdose may be similar to those resulting from excessive stimulation of dopamine receptors (eg, nausea, vomiting, complaints of stomach pain, postural hypotension, confusion/psychosis, or hallucinations). If necessary, supportive measures should be used to remove any remaining unabsorbed drug and maintain blood pressure. In addition, it may be advisable to administer dopamine antagonist drugs.

Interaction with other drugs

Concomitant use of Caberlin 0.5 with other drugs, especially ergot alkaloids, in the postpartum period was not associated with obvious interactions that altered the effectiveness and safety of this drug. Although there is no data on the interaction of cabergoline with other ergot alkaloids, the simultaneous use of these drugs during long-term treatment with Caberlin 0.5 is not recommended. Since Caberlin 0.5 exerts its therapeutic effect by direct stimulation of dopamine receptors, its combined use with dopamine receptor antagonists (for example, phenothiazines, butyrophenones, thioxanthenes and metoclopramide) is not recommended, since these drugs may reduce the prolactin-lowering effect of cabergoline. Like other ergot derivatives, Caberlin 0.5 should not be used with macrolide antibiotics (for example, erythromycin) due to increased systemic bioavailability of cabergoline

Precautionary measures

General As with other ergot alkaloids, Caberlin 0.5 should be used with caution in patients with severe cardiovascular disease, Raynaud's syndrome, gastric ulcers or gastrointestinal bleeding, or a history of serious mental illness. There is no data on the effect of alcohol on cabergoline tolerance. Symptomatic arterial hypotension can develop when using Caberlin 0.5 for any indication. Hepatic impairment In patients with severe hepatic impairment undergoing long-term therapy with cabergoline, it may be advisable to consider the use of reduced doses. In contrast to healthy volunteers and individuals with lesser degrees of liver failure, patients with severe liver dysfunction (class C on the Child-Pugh scale) showed an increase in AUC with a single dose of 1 mg. Renal failure No differences in the pharmacokinetics of cabergoline were observed in patients with moderate or severe kidney disease. The pharmacokinetics of cabergoline in patients with end-stage renal failure or in patients on hemodialysis have not been studied, so the drug should be used with caution in such patients. Postural hypotension During the period of use of Caberlin 0.5, postural hypotension was observed. Therefore, caution should be used when using it with drugs that can also lower blood pressure. Fibrosis, cardiac valvulopathy and other critical events Fibrous and serous inflammations such as pleurisy, pleural effusion, pleural fibrosis, pulmonary fibrosis, pericarditis, pericardial effusion, cardiac valvulopathy involving one or more valves (aortic, mitral and tricuspid), or retroperitoneal fibrosis , occur after long-term use of ergoline derivatives with agonistic activity against serotonin 5HT2B receptors such as cabergoline. In some cases, the symptoms and clinical manifestations of cardiac valvulopathy are alleviated after discontinuation of cabergoline. The erythrocyte sedimentation rate (ESR) in hydrothorax/fibrosis has been found to be elevated above normal. If ESR increases to values higher than normal, a chest x-ray is recommended. After discontinuation of cabergoline when a diagnosis of pleurisy/pulmonary fibrosis was made, an improvement in the patient's clinical picture was reported. Valvulopathy has been observed with cumulative doses, so patients should be treated with low effective doses. During each visit, the benefit-risk ratio for the patient must be re-evaluated in order to determine the advisability of continuing treatment with Caberlin 0.5. Before initiating long-term treatment, all patients should undergo cardiovascular evaluation, including an echocardiogram, to determine the presence of asymptomatic valvular disease. It is also advisable to obtain baseline measurements of ESR or other markers of inflammation, pulmonary function (chest x-ray), and renal function prior to treatment. It is unknown whether taking Caberlin 0.5 can worsen the disease in patients with valvular regurgitation. It has been established that in the presence of fibrotic changes in the valves, patients should not receive treatment with Caberlin 0.5. For long-term treatment: Since fibrotic disorders may have an insidious onset, regular monitoring should be carried out for possible signs of progression of fibrosis. Therefore, during treatment, attention should be paid to the following symptoms: - pleuropulmonary diseases such as dyspnea, shortness of breath, persistent cough or chest pain; - renal failure or ureteral/abdominal vascular obstruction, which may present with low back/flank pain and lower extremity edema, as well as any abdominal masses or tenderness that may indicate retroperitoneal fibrosis; - heart failure: cases of valvular or pericardial fibrosis often manifest as heart failure. Therefore, when appropriate symptoms appear, valvular fibrosis (and constrictor pericarditis) must be excluded. Clinical diagnostic monitoring for the development of fibrotic disorders is mandatory. The first echocardiography should be performed within 3-6 months after the start of treatment; In the future, the frequency of echocardiographic examinations should be determined according to individual clinical signs, special attention should be paid to the above symptoms, but monitoring should be carried out at least every 6-12 months. The use of Caberlin 0.5 should be discontinued if the ECG reveals signs of new or worsening of existing valvular regurgitation, valve restriction or sealing of the valve leaflets. The need for other clinical examinations (eg, physical examination, auscultation, radiography, CT scan) should be determined on an individual basis. Appropriate additional studies, such as determination of ESR and serum creatinine levels, should be performed if necessary to confirm the diagnosis of fibrotic disorders. Arterial hypotension Within 6 hours after using Caberlin 0.5, symptomatic hypotension may develop, therefore, with extreme caution, Caberlin 0.5 should be prescribed simultaneously with other drugs that can lower blood pressure. Given the half-life, the hypotensive effect may persist for several days after discontinuation of the drug. During the first 3-4 days after starting therapy, monitoring with regular blood pressure measurements is recommended. In postpartum studies, decreased blood pressure (>20 mmHg systolic and >10 mmHg diastolic) has been reported to occur 3 to 4 days after a single 1 mg dose of cabergoline. Undesirable effects were usually observed during the first two weeks, after which their manifestations decreased or disappeared altogether. Impulse control disorders Patients should be closely monitored for the occurrence of impulse control disorders. Patients and their environment should be warned about possible changes in behavior that indicate a violation of impulse control, such as pathological gambling, increased libido, hypersexuality, impulsive desire to make purchases, impulsive overeating when using dopamine agonists, including cabergoline. In this case, you should reduce the dose or stop taking the drug. Inhibition/suppression of physiological lactation Like other ergot alkaloids, Caberlin 0.5 should be used in patients with pregnancy-related hypertension only in cases where the expected benefit of treatment outweighs the risk. A single dose of 0.25 mg should be avoided during breastfeeding to avoid the development of postural hypotension. Treatment of hyperprolactinemia The underlying cause of hyperprolactinemia should be investigated before starting treatment with Caberlin 0.5, since hyperprolactinemia, accompanied by amenorrhea/galactorrhea and infertility, may be associated with pituitary tumors. When an effective therapeutic dose is achieved, it is recommended to monitor the level of prolactin in the blood serum once a month; normalization of the level of prolactin in the serum is usually observed within 2-4 weeks. After discontinuation of Caberlina 0.5, a relapse of hyperprolactinemia is usually observed. However, in some patients, persistent suppression of prolactin levels was observed for several months. Before starting treatment for hyperprolactinemia, the condition of the pituitary gland should be diagnosed. The drug restores ovulation and fertility in women with hyperprolactinemic hypogonadism, therefore it is recommended to carry out a pregnancy test every 4 weeks during the amenorrhea period and each time after the restoration of menstruation if their delay is more than 3 days. Women who do not wish to become pregnant should use mechanical contraception during therapy and after discontinuation of the drug until anovulation returns. If pregnancy occurs during treatment, taking Caberlin 0.5 should be discontinued. As a precaution, women who become pregnant should be monitored for signs of pituitary enlargement, as there is a possibility that an existing pituitary tumor will increase in size during pregnancy. Before prescribing the drug, pregnancy should be excluded. Given the limited clinical experience with the drug and its long half-life, as a preventive measure, women planning pregnancy are recommended to stop using Caberlin 0.5 a month before expected conception after achieving a regular ovulatory cycle. For patients taking the drug for a long time, it is recommended to conduct regular gynecological examinations, including cytological examinations of the cervix and endometrium. Drowsiness/sudden sleepiness Caberlin 0.5 may cause drowsiness. Dopamine agonists may cause sudden sleep onset in patients with Parkinson's disease. The above information should be communicated to patients and advised to be careful while driving or operating other automated systems during the period of treatment with Kaberlin 0.5. Patients who have experienced drowsiness and/or episodes of sudden sleep should refrain from driving vehicles or operating other automated systems. For such patients, dose reduction or discontinuation of treatment should be considered. Other This medicine contains lactose. Patients with hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not use this drug.

Storage conditions

Store at a temperature not exceeding 30 °C. Keep out of the reach of children.