Cabergoline

Pharmacological properties

cabergoline, a synthetic ergot alkaloid and ergoline derivative, has a pronounced and lasting prolactin-lowering effect.

The prolactin-lowering effect is dose-dependent. Decrease in the level of prolactin in blood plasma begins 3 hours after taking the drug Alactin and lasts for 2-3 weeks. The effect of prolonged action means that a single dose is sufficient to stop the stimulation of milk secretion. In the treatment of hyperprolactinemia, plasma prolactin levels normalize within 2-4 weeks after reaching the optimal dose. Prolactin levels may still decline significantly for several months after treatment is discontinued.

As for the endocrinological effects of cabergoline that are not related to the antiprolactinemic effect, the data obtained in animal experiments confirm that the studied drug has a selective effect without affecting the main secretion of other pituitary hormones or cortisol.

The pharmacodynamic effect of cabergoline, which does not correlate with the therapeutic effect, concerns only a decrease in blood pressure. The maximum hypotensive effect of a single dose of cabergoline is usually achieved within the first 6 hours after taking the drug, and the maximum decrease in blood pressure and the frequency of occurrence of such an effect are dose-dependent.

Pharmacokinetics Absorption. Cabergoline is rapidly absorbed in the gastrointestinal tract after oral administration, C_max in blood plasma is reached after 0.5-4 hours. Eating does not affect the absorption and distribution of cabergoline.

Distribution. In vitro experiments showed that cabergoline in concentrations of 0.1–10 ng / ml binds to plasma proteins by 41–42%.

Biotransformation. The main metabolite identified in urine is 6-alyl-8β-carboxy-ergoline, which accounts for 4–6% of the dose. Three other metabolites account for a total of 3% of the dose. The activity of metabolites in relation to the inhibition of prolactin secretion, studied in vitro, is significantly lower than cabergoline.

T_½ long-term cabergoline: 79–115 hours in patients with hyperprolactinemia.

10 days after taking the drug, approximately 18 and 72% of the dose is in the urine and feces, respectively. 2-3% of the dose is determined in the urine unchanged.

Indications

Inhibition / suppression of physiological lactation

Alactin is prescribed to inhibit physiological postpartum lactation immediately after childbirth or to suppress lactation established in the following cases:

• after childbirth, if the mother decided not to breast-feed the baby or when breast-feeding is contraindicated for the mother or baby for medical reasons;
• after giving birth to a dead fetus or abortion.

Treatment of hyperprolactinemic conditions

Alactin is indicated for the treatment of disorders associated with hyperprolactinemia, including amenorrhea, oligomenorrhea, anovulation and galactorrhea. The drug is indicated for the treatment of patients with prolactin-secreting pituitary adenomas (micro- and macro-prolactinomas), idiopathic hyperprolactinemia or the “empty” Turkish saddle syndrome with concomitant hyperprolactinemia, which are the main pathological conditions responsible for the aforementioned clinical manifestations.

Application

Alactin is prescribed orally.

In order to reduce the risk of side effects from the gastrointestinal tract, it is recommended to take cabergoline with meals.

Inhibition / suppression of postpartum lactation. To inhibit postpartum lactation, Alactin should be used during the first 24 hours after birth. The recommended therapeutic dose is 1 mg of cabergoline once. To suppress existing lactation - 0.25 mg every 12 hours for 2 days (total dose - 1 mg).This dosage regimen is better tolerated by women who have decided to suppress lactation than a single dose, and it is accompanied by a lower incidence of adverse events, especially symptoms of hypertension.

Treatment of hyperprolactinemic conditions. The recommended initial dose of Alactin is 0.5 mg once a week or ½ tablets of 0.5 mg 2 times a week (for example, on Monday and Thursday). If necessary, you can gradually increase the dose under the supervision of a doctor - by 0.5 mg / week with a monthly interval until a therapeutic effect is achieved. Typically, the therapeutic dose is 1 mg / week and can range from 0.25 to 2 mg / week.

The maximum dose should not exceed 3 mg / day.

A weekly dose of the drug can be prescribed once or distributed into 2 or more receptions per week, depending on tolerability.

The distribution of the weekly dose in several doses is recommended when the weekly dose is 1 mg.

When selecting a dose, patients should be examined in order to determine the minimum effective therapeutic dose. Normalization of prolactin levels is usually observed within 2-4 weeks of treatment.

After the cancellation of cabergoline, a relapse of hyperprolactinemia is usually noted.

Elderly patients. Experience with cabergoline in the elderly with hyperprolactinemia is limited.

Available data indicate no particular risk.

Dose reduction or discontinuation of treatment. Consideration should be given to reducing the dose or stopping treatment if patients have:

• drowsiness or sudden falling asleep;
• impaired liver function.

Contraindications

Hypersensitivity to cabergoline, other ergot alkaloids or any component of the drug.

A history of fibrotic lung disease, pericardium and retroperitoneal space.

Hepatic insufficiency and toxemia of pregnant women.

The simultaneous use of antipsychotic drugs.

For long-term treatment: signs of damage to the heart valves, which are determined by echocardiography before treatment.

Postpartum hypertension or uncontrolled hypertension.

Preeclampsia, eclampsia.

A history of psychosis or a risk of developing postpartum psychosis.

Side effects

Dose-dependent and their severity may decrease with a gradual decrease in dose.

In patients with known intolerance to dopaminergic drugs, the likelihood of adverse events can be reduced if treatment with cabergoline is started with reduced doses, for example 0.25 mg once a week, followed by a gradual increase until a therapeutic dose is reached. In the event of persistent or severe side effects, a temporary dose reduction followed by a more gradual increase, for example, by 0.25 mg / week every 2 weeks, can improve tolerance to the drug.

From the vascular system: arterial hypotension with prolonged use, postural hypotension, peripheral vasospasm, fainting, hot flashes.

From the side of the heart: cardiac valvulopathy (including regurgitation) and related disorders (pericarditis and pericardial effusion), heart palpitations, angina pectoris.

From the musculoskeletal system: cramps of the lower extremities, muscle weakness.

On the part of the skin and subcutaneous tissue: skin reactions, including alopecia, rash, itching, allergic skin reactions.

From the immune system: hypersensitivity reactions.

Mental disorders: depression, aggression, hypersexuality, pathological gambling, increased libido, crazy ideas, hallucinations, psychotic disorders.

From the nervous system: dizziness, headache, vertigo, paresthesia, syncope, tremor, sudden falling asleep, transient hemianopsia, drowsiness.

From the digestive tract: abdominal pain and epigastrium, dyspepsia, nausea, gastritis, constipation, vomiting.

From the reproductive system: pain in the mammary glands.

From the side of the organ of vision: visual impairment.

From the respiratory system: dyspnea, respiratory failure, respiratory failure, nosebleeds, pleural effusion, fibrosis (including pulmonary fibrosis), pleural fibrosis, chest pain.

From the hepatobiliary system: impaired liver function.

Common disorders: asthenia, fatigue, edema, peripheral edema.

Laboratory studies: a decrease in hemoglobin in women with amenorrhea within 1 month after menstruation, an asymptomatic decrease in blood pressure (≥20 mmHg - systolic and ≥10 mmHg - diastolic) can occur 1 time during the first 3-4 days after birth, increased levels of blood CPK, impaired liver function indicators.

Description of individual adverse reactions

Violation of control over motivation: pathological gambling, increased libido, hypersexuality, impulsive desire to make a purchase, overeating, impulsive eating with dopamine agonists, including cabergoline.

The following adverse reactions have also been noted: nervousness, dysmenorrhea, acne, pain, arthralgia, rhinitis, dry mouth, diarrhea, bloating, throat irritation, toothache, symptoms similar to the common cold, periorbital edema, peripheral edema, anorexia, insomnia, increase / weight loss, impaired concentration, arousal.

special instructions

Are common. as with other ergot alkaloids, alactin should be used with caution in patients with severe cardiovascular disease, Raynauds syndrome, gastric ulcer or gastrointestinal bleeding, a history of serious mental illness.

There is no evidence of the effect of alcohol on cabergoline tolerance.

Symptomatic hypertension can develop with the use of cabergoline for any indication.

Liver failure. In patients with severe hepatic insufficiency undergoing prolonged therapy with cabergoline, it is advisable to consider the use of the drug in reduced doses. In contrast to healthy volunteers and those with less liver failure, patients with severely impaired liver function (Child-Pugh class C) showed an increase in AUC with a single dose of the drug in a dose of 1 mg.

Renal failure. Differences in the pharmacokinetics of cabergoline in moderate to severe renal disease were not noted. The pharmacokinetics of cabergoline in patients with end-stage renal failure or in patients undergoing hemodialysis have not been investigated, therefore, such patients should be used with caution.

Postural hypotension. During the use of Alactin, postural hypotension was observed. Therefore, it is necessary to use it with caution in combination with drugs that can also lower blood pressure.

Fibrosis, cardiac valvulopathy and other critical conditions. Fibrous and serous inflammations, such as pleurisy, pleural effusion, pleural fibrosis, pulmonary fibrosis, pericarditis, pericardial effusion, cardiac valvulopathy, affecting ≥1 valves (aortic, mitral and tricuspid), or retroperitoneal fibrosis occur after prolonged use of such ergoline activity against serotonin 5-HT_2Breceptors like cabergoline. In some cases, the severity of symptoms and clinical manifestations of cardiac valvulopathy decreases after the withdrawal of cabergoline.

It was revealed that ESR with pleural effusion / fibrosis exceeds the norm. With an increase in ESR to values ​​exceeding the norm, it is recommended that chest radiography be performed.After canceling cabergoline, a diagnosis of pleurisy / pulmonary fibrosis was reported to improve the clinical condition of the patient.

Valvulopathy was noted with cumulative doses, so patients should be given the lowest effective dose. During each visit to the doctor, it is necessary to re-evaluate the ratio of benefit and risk for this patient in order to determine the feasibility of continuing treatment with cabergoline.

Prior to the start of long-term treatment, all patients should undergo a cardiovascular examination, including echocardiography, to determine the presence of asymptomatic valve disease. It is also advisable to determine the baseline levels of ESR or other markers of inflammation, pulmonary function (chest x-ray) and kidney function before treatment.

It is not known whether taking cabergoline can worsen the course of the disease in patients with valvular regurgitation. It has been established that in the presence of fibrotic valve changes, patients should not be treated with cabergoline.

During long-term treatment: since the presence of fibrotic changes may have a hidden beginning, it is necessary to regularly monitor the likely signs of progression of fibrosis. Thus, during therapy, attention should be paid to the following symptoms:

• pleuropulmonary disease - dyspnea, shortness of breath, persistent cough or chest pain;
• renal failure or obstruction of the ureter / abdominal vessels, which can manifest as pain in the lower back / side and swelling of the lower limb, as well as any formations in the abdominal cavity or soreness, which may indicate the presence of retroperitoneal fibrosis;
• heart failure: cases of valvular or pericardial fibrosis often manifest as heart failure. Therefore, when the corresponding symptoms appear, it is necessary to exclude valvular fibrosis (and constrictor pericarditis).

Clinical diagnostic monitoring of 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 echocardiography studies should be determined in accordance with individual clinical signs, special attention should be paid to the above symptoms, but monitoring is recommended at least every 6-12 months.

The use of cabergoline should be discontinued if signs of new or worsening of existing valve regurgitation, restriction of the valve, or tightening of the valve cusps are detected on the echocardiography.

The need for other clinical examination methods (for example, physical examination, auscultation of the heart, radiography, CT scan) should be determined individually.

Corresponding additional studies, such as determining the level of ESR and creatinine in blood plasma, are carried out if necessary to confirm the diagnosis of fibrotic disorders.

Arterial hypotension. Within 6 hours after the use of cabergoline, symptomatic hypotension may develop, therefore, with special caution, cabergoline should be prescribed simultaneously with other drugs that can reduce blood pressure. Considering T_½ hypotensive effect may persist for several days after discontinuation of the drug. During the first 3-4 days after the start of therapy, monitoring with regular measurements of blood pressure is recommended.

It was reported that in studies of the postpartum period, there have been cases of a decrease in blood pressure (≥20 mm Hg - systolic and ≥10 mm Hg - diastolic) 3-4 days after taking cabergoline in a single dose of 1 mg. Undesirable effects were usually noted during the first 2 weeks, after which their manifestations decreased or completely disappeared.

Violation of control over motives.Patients should be carefully monitored for impaired control of motives. Patients and their environment should be warned of possible changes in behavior that indicate a violation of control over motives, such as pathological gambling, increased libido, hypersexuality, an impulsive desire to make a purchase, overeating, impulsive eating with dopamine agonists, including cabergoline. In this case, reduce the dose or stop taking the drug.

Inhibition / suppression of physiological lactation. Like other ergot alkaloids, Alactin should be used in patients with hypertension due to pregnancy only in cases where the expected benefits of treatment outweigh the risk.

A single dose of 0.25 mg should be avoided in women who are breastfeeding, in order to avoid the development of postural hypotension.

Treatment of hyperprolactinemia. The main cause of hyperprolactinemia should be established before starting treatment with cabergoline, since hyperprolactinemia, accompanied by amenorrhea / galactorrhea and infertility, may be associated with pituitary tumors.

When an effective therapeutic dose is reached, it is recommended to monitor the level of prolactin in the blood plasma once a month, normalization of the level of prolactin in the blood plasma is usually recorded for 2-4 weeks.

After the cancellation of cabergoline, as a rule, a relapse of hyperprolactinemia occurs. However, in some patients, persistent inhibition of prolactin levels developed over several months.

Before starting treatment of hyperprolactinemia, a diagnosis of the pituitary gland should be carried out. The drug restores ovulation and fertility in women with hyperprolactinemic hypogonadism, therefore it is recommended to conduct a pregnancy test every 4 weeks during the period of amenorrhea and every time after the restoration of menstruation, if their delay is more than 3 days. Women who do not plan pregnancy should use mechanical contraception during therapy and after discontinuation of the drug until anovulation returns. If pregnancy occurs during treatment, cabergoline should be discontinued. As a precaution, women who become pregnant should be monitored to detect signs of an increase in the pituitary gland, since it is possible to increase the volume of an existing pituitary tumor during pregnancy. Before prescribing the drug, pregnancy should be excluded. Given the limited clinical experience with the drug and its long T_½, as a precaution for women planning a pregnancy, it is recommended that after achieving a regular ovulatory cycle, stop using cabergoline one month before the expected conception. For patients taking the drug for a long time, it is recommended to conduct regular gynecological examinations, including cytological studies of the cervix and endometrium.

Drowsiness / sudden falling asleep. Cabergoline can cause drowsiness. Dopamine agonists can cause sudden falling asleep in patients with Parkinsons disease. The above information should be reported to patients and advised to be careful while driving or working with other automated systems during the period of treatment with cabergoline. Patients with marked drowsiness and / or sudden falling asleep should refrain from driving vehicles or working with other automated systems. For such patients, consideration should be given to reducing the dose or discontinuing treatment.

Misc. This medicine contains lactose.Patients with hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not use this drug.

During pregnancy and breastfeeding. Pregnancy. Adequate and well-controlled studies of the use of cabergoline in pregnant women have not been conducted. Animal studies have shown no teratogenic effect, however, decreased fertility, as well as embryotoxicity associated with pharmacodynamic activity have been reported.

Cases of the occurrence of large congenital malformations or premature termination of pregnancy after cabergoline therapy in pregnant women have been reported. The most common neonatal abnormalities were musculoskeletal disorders and cardiopulmonary abnormalities. Information on perinatal disorders and the further development of infants after intrauterine action of cabergoline is not available. According to available publications, the prevalence of large congenital malformations in the general population is ≥6.9%. The frequency of congenital anomalies varies in different populations. It is not possible to determine exactly whether there is an increased risk.

Pregnancy should be ruled out before taking cabergoline and pregnancy should be avoided for at least 1 month after the end of therapy. Since in patients with hyperprolactinemia T_½ cabergoline is 79–115 hours, after establishing a regular ovulatory cycle, women who plan to become pregnant should stop taking cabergoline 1 month before the planned conception. This will prevent the possible effect of the drug on the fetus and will not impede the possibility of fertilization, as in some cases the ovulatory cycle persists for 6 months after drug withdrawal. If fertilization occurred during treatment, therapy should be discontinued after confirmation of pregnancy in order to limit the effect of the drug on the fetus.

After the cancellation of cabergoline, contraceptives must be used for at least 4 weeks.

Cabergoline restores ovulation and fertility in women with hyperprolactinemic hypogonadism: since pregnancy can occur before the menstrual cycle is restored, it is recommended to conduct a pregnancy test during the amenorrhea period after menstruation has resumed - every time menstruation is delayed for more than 3 days. Women who do not plan pregnancy are recommended to use effective non-hormonal contraceptives during treatment and after the cancellation of cabergoline.

In view of the long T_½ and limited data on the safety of the effect of cabergoline on the fetus for women who are planning a pregnancy, fertilization is recommended at least 1 month after stopping cabergoline. After pregnancy, women should be monitored to detect signs of an increase in the pituitary gland, since during pregnancy, growth of existing pituitary tumors may be noted.

Lactation. Due to its ability to suppress lactation, cabergoline cannot be used in women with hyperprolactinemic disorders who want to breastfeed.

Cabergoline and / or its metabolites were excreted in milk when tested in rats. There is no information on the allocation of human breast milk; however, women should be advised not to breast-feed if lactation suppression with cabergoline is ineffective.

Children. The safety and effectiveness of the drug have not been studied in children under the age of 16 years.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. In the early days of taking cabergoline, patients should be cautioned against engaging in activities requiring quick and accurate reactions.

Patients who are treated with cabergoline and who have drowsiness and / or sudden episodes of falling asleep are advised to refrain from driving vehicles and activities that require increased attention until such episodes and drowsiness disappear.

Interactions

Despite the lack of data on the interaction of alactin with other ergot alkaloids, concomitant therapy with these drugs for a long time is not recommended.

Since Alactin realizes its effect by direct stimulation of dopamine receptors, the simultaneous use of dopamine antagonists (e.g. phenothiazines, butyrophenones, thioxanthenes, metoclopramide) is not recommended, so as not to reduce the clinical effect of the drug.

The drug should not be used with macrolide antibiotics (erythromycin) due to increased systemic bioavailability of cabergoline.

It is necessary to take into account the interaction of Alactin with other drugs that reduce blood pressure.

Overdose

If you accidentally take the drug in very high doses, nausea, vomiting, stomach upsets, arterial hypotension, impaired consciousness (psychosis, hallucinations) may develop. in such cases, emergency medical care is necessary.

In case of an overdose, general measures should be taken regarding the removal of the drug, which has not yet been absorbed, and, if necessary, to maintain blood pressure. In addition, dopamine antagonists (e.g. domperidone, metoclopramide) may be recommended.

Storage conditions

In the original packaging for protection against moisture at a temperature not exceeding 30 ° C. Do not remove the mini bag with silica gel to adsorb moisture from the bottle.