Dostinex - tablets for stopping lactation. Dostinex - instructions for use of tablets to stop lactation, composition, side effects and analogues Dostinex lactation tablets instructions
Dostinex tablets are prescribed to suppress lactation in the postpartum period, but in order for the medication not to cause harm, you must carefully read the instructions for use that is attached to each pack before starting therapy.
Release form
The drug is available in the form of white, flat oval tablets. On one side there are the letters "P" and "U", which are separated by a risk, on the other - the number "700" and 2 dashes located above and below the numbers.
As an active ingredient, the drug contains carbergoline, in 1 tablet it is 0.5 mg. In addition to it, the composition of the tablets includes indifferent ingredients, milk sugar and 2-amino-4-methylpentanoic acid.
Cabergoline belongs to ergoline derivatives and is a dopamine receptor agonist.
Substance entering the body:
- activates dopamine d2-receptors of lactotropic cells localized in the adenohypophysis;
- has a strong and prolonged prolactin-lowering effect;
- has a central dopaminergic effect if you drink the drug in dosages greater than required to reduce the level of lactogenic hormone in the body;
- acts selectively, does not change the production of hydrocortisone and the production of other hormones by the pituitary gland, except for mammotropin;
- lowers blood pressure (this is not a therapeutic effect, it is dose-dependent and is most pronounced in the first 6 hours after taking the medication).
Indications for use
Dostinex, instructions for use which contains information on the purpose of the drug, is used to:
Contraindications
Dostinex, the instructions for use of which informs in which cases the drug is prohibited from prescribing, is not recommended if there is:
- intolerance to the composition of the drug;
- proliferation of connective tissue with the appearance of scars, resulting in pathologies of the heart and lungs, including in history;
- intolerance to milk sugar, lack of lactase, malabsorption of monosaccharides;
- age under 16;
- hypersensitivity to ergot alkaloids.
You should not take the medication for a long time if, before starting therapy, a violation of the function of the heart valves was confirmed by echocardiography.
With caution, treatment should be carried out if a woman has the following pathologies:
- bleeding from the gastrointestinal tract;
- peptic ulcer;
- severe violations of the liver;
- serious cardiovascular pathologies;
- Raynaud's disease;
- severe psychotic disorders, memory problems, decreased mental performance and other cognitive functions, including in the past;
- arterial hypertension that appeared during gestation or after childbirth.
Due to the likelihood of orthostatic collapse, Dostinex should be taken with caution with medications that lower blood pressure. Due to the lack of controlled scientific trials, it is possible to prescribe the drug to pregnant women when the benefit to the mother outweighs the harm to the fetus.
When conception occurs against the background of treatment with a prolactin-reducing agent, the question of the advisability of its further use should be decided. If therapy is continued, then the woman should be under the constant supervision of a doctor because of the risk of an increase in the size of the pituitary gland.
According to statistics, the treatment of hyperprolactinemia with a drug at a dosage of up to 2 mg per week did not increase the number of spontaneous abortions, preterm births, multiple pregnancies and anomalies in newborns.
Negative effect on the body
Dostinex, instructions for use to which warns of adverse reactions, can provoke an undesirable response of the body:
The effectiveness of taking pills
After oral administration, the drug is rapidly absorbed from the digestive tract, its highest concentration in the bloodstream is observed after 30-240 minutes.
A decrease in the level of lactogenic hormone in the blood is noted 3 hours after taking the pill and remains low for 1-3 weeks in women with hyperprolactinemia and up to 2-3 weeks in the postpartum period. The prolactin-lowering effect is dose-dependent in terms of strength and duration of action.
Eating does not change the absorption and distribution rate of the active ingredient in the body.
After the optimal treatment regimen for hyperprolactinemia is selected, the amount of lactogenic hormone should be checked once a month. Normalization of mammotropin is observed in most women within 14-28 days.
Taking the drug for mastitis
If mastitis occurs, Dostinex is prescribed in combination with antimicrobial agents, especially if the disease occurs with the appearance of pus. The drug is taken to stop the production of milk, as it can increase the severity of the pathological process.
The drug is prescribed in this case, 0.5 tablet (0.25 mg) twice a day, the course of therapy is 2 days. For the duration of therapy, breastfeeding is interrupted, since there is no data on whether the active substance is excreted in milk, but it is known that it remains in the body for up to 2-3 weeks.
How to take pills correctly
Dostinex should be taken with meals in the dosages prescribed in the instructions:
| Indications | Reception scheme |
| To prevent milk secretion | 1 time on the first day after delivery at a dosage of 1 mg, which corresponds to 2 tablets |
| To complete breastfeeding | The drug is drunk half a tablet twice a day, the course of administration is 2 days, the course dose is 1 mg |
| In pathological processes caused by high levels of lactogenic hormone | Dosage:
|
Do I need to express milk after taking Dostinex?
Dostinex suppresses the production of prolactin and reduces the amount of milk, so usually a woman does not need to express milk. After taking Dostinex, you need to express milk from the breast, unless the mammary glands are swollen and sore. This can be done manually or with a breast pump.
It is not necessary to express milk to the end, the procedure is carried out only in order to get rid of engorgement and pain in the chest.
With severe pain, before pumping, you can drink an anesthetic and place the mammary gland under warm water or carry out all the manipulations in the shower. After the procedure, it is required to apply a cold compress to the breast, which will slow down the production of milk.
It is also necessary to express milk if a woman decides to interrupt feeding only for a while, for example, due to illness or taking medications that are incompatible with breastfeeding.
Recovery of lactation
To restore lactation after taking Dostinex, you need to follow a number of rules:
As with other drugs containing ergot, Dostinex must be used with caution. Instructions for use warns that the drug is a prescription drug, so self-medication is unacceptable.
Article formatting: Lozinsky Oleg
Video about Dostinex
Feedback on the drug Dostinex, the effect of the drug:
Dosage form
Tablets 0.5 mg
Compound
One tablet contains
active substance - cabergoline 0.5 mg;
Excipients: lactose anhydrous, leucine.
Description
Tablets of oblong shape, with a flat surface, white, marked "P" and "U", with a risk on one side and the number "700" - on the other side with short notches above and below the central "0" in the number.
Pharmacotherapeutic group
Other drugs for the treatment of gynecological diseases.
Prolactin secretion inhibitors.
Cabergoline
ATX code G02CB03
Pharmacological properties
Pharmacokinetics
Cabergoline is rapidly absorbed from the gastrointestinal tract, the maximum concentration in blood plasma is reached after 0.5 - 4 hours, the connection with blood plasma proteins is 41 - 42%. The half-life of cabergoline, estimated from the rate of excretion in the urine, is 63-68 hours in healthy volunteers and 79-115 hours in patients with hyperprolactinemia. Due to the long half-life, the state of equilibrium concentration is reached after 4 weeks. 10 days after taking the drug in the urine and feces, about 18% and 72% of the dose taken, respectively, are found, and the proportion of unchanged drug in the urine is 2-3%. The main product of cabergoline metabolism identified in urine is 6-allyl-8β-carboxy-ergoline at concentrations up to 4-6% of the dose taken. The content in the urine of 3 additional metabolites does not exceed 3% of the dose taken. Metabolic products have been found to have a significantly lesser effect on suppressing prolactin secretion compared to cabergoline. The biotransformation of radiolabelled cabergoline has also been studied in healthy volunteers and was rapid and significant.
Experiments in vitro showed that cabergoline at concentrations of 0.1-10 ng / ml binds to plasma proteins by 41-42%.
Eating does not affect the absorption and distribution of cabergoline.
Pharmacodynamics
Dostinex® is a dopaminergic derivative of ergoline and is characterized by a prolactin-lowering effect due to direct stimulation of D2-dopamine receptors of lactotropic pituitary cells. In addition, when taken at higher doses compared to those for lowering serum prolactin levels, Dostinex® has a central dopaminergic effect due to stimulation of D2 receptors.
A decrease in the concentration of prolactin in the blood plasma is observed within 3 hours after taking the drug and persists for 7-28 days in healthy volunteers and patients with hyperprolactinemia, and up to 14-21 days in women in the postpartum period.
Dostinex® has a strictly selective effect, does not affect the basal secretion of other pituitary hormones and cortisol. The prolactin-lowering effect of the drug is dose-dependent both in terms of severity and duration of action.
The pharmacodynamic effects of Dostinex®, not associated with a therapeutic effect, include only a decrease in blood pressure (BP). With a single dose of the drug, the maximum hypotensive effect is observed within the first 6 hours and is dose-dependent.
Indications for use
Prevention of physiological lactation after childbirth
Suppression of already established postpartum lactation:
a) after childbirth, if the mother does not want to breastfeed, or if breastfeeding is contraindicated for the mother or child for medical reasons;
b) after the birth of a dead fetus or abortion
Treatment of disorders associated with hyperprolactinemia, including amenorrhea, oligomenorrhea, anovulation, galactorrhea
Prolactin-secreting pituitary adenomas (micro- and macroprolactinomas); idiopathic hyperprolactinemia, syndrome of "empty" Turkish saddle in combination with hyperprolactinemia.
Dosage and administration
Inside, during meals.
Prevention of lactation: 1 mg once (2 tablets of 0.5 mg), on the first day after childbirth.
Suppression of established lactation: 0.25 mg (1/2 tablet) twice a day every 12 hours for two days (total dose is 1 mg). In order to reduce the risk of orthostatic hypotension in breastfeeding mothers, a single dose of Dostinex® should not exceed 0.25 mg.
Treatment of disorders associated with hyperprolactinemia: The recommended starting dose is 0.5 mg per week in one dose (1 tablet of 0.5 mg) or in two doses (1/2 tablet of 0.5 mg, for example, on Monday and Thursday). Increasing the weekly dose should be carried out gradually - by 0.5 mg with a monthly interval until the optimal therapeutic effect is achieved. The therapeutic dose is usually 1 mg per week, but may range from 0.25 to 2 mg per week. The maximum dose for patients with hyperprolactinemia should not exceed 4.5 mg per week.
Depending on tolerance, the weekly dose can be taken once or divided into 2 or more doses per week. Dividing the weekly dose into several doses is recommended when prescribing the drug at a dose of more than 1 mg per week.
During dose selection, patients should be observed to determine the lowest effective dose. The level of prolactin in the blood serum should be determined monthly, since its normalization is usually observed within 2-4 weeks after the selection of an effective dose.
After discontinuation of the drug Dostinex®, a relapse of hyperprolactinemia is usually observed. However, in some cases, there is a persistent decrease in prolactin levels for several months. In most women, ovulatory cycles persist for at least 6 months after Dostinex is discontinued.
In patients with hypersensitivity to dopaminergic drugs, the likelihood of developing side effects can be reduced by starting therapy with Dostinex® at a lower dose (for example, 0.25 mg once a week), followed by a gradual increase until a therapeutic dose is reached. To improve the tolerability of the drug in the event of severe side effects, it is possible to temporarily reduce the dose, followed by a more gradual increase (for example, an increase of 0.25 mg per week every two weeks).
The duration of treatment is determined by the attending physician.
Side effects
Very common (≥ 1/10)
Cardiac valvulopathy (including valvular regurgitation) and related disorders (pericarditis and pericardial effusion)
Headache, vertigo (dizziness)
Nausea, dyspepsia, gastritis, abdominal pain
Asthenia, fatigue
Often (≥1/100 to< 1/10 )
Drowsiness
Depression
Orthostatic hypotension (with long-term use, Dostinex usually has a hypotensive effect), postural hypotension, hot flashes
Constipation, vomiting
Pain in the mammary glands
Asymptomatic low blood pressure (systolic blood pressure ≥ 20 mmHg and diastolic blood pressure ≥ 10 mmHg)
Infrequently (≥1/ 1000 to< 1 / 100 )
Cardiopalmus
Dyspnea, exudative pleurisy, fibrosis (including pulmonary fibrosis), epistaxis
hypersensitivity reactions
Transient hemianopia, syncope, paresthesia
Increased libido
Spasm of the fingers
Edema, peripheral edema
Rash, alopecia (hair loss)
Leg muscle cramps
Decreased hemoglobin levels during the first few months after the return of menstruation in women with amenorrhea
Rarely (≥1/ 10000 to< 1 / 1000 )
Pain in the epigastric region
Very rarely (< 1 / 10000 )
Pleurofibrosis
unknown
angina pectoris
Respiratory disorders, respiratory distress, pleurisy, chest pain
sudden sleep, tremor
visual impairment
Aggressiveness, delusions, hypersexuality, pathological gambling, psychotic disorders, hallucinations
Impaired liver function
Increased levels of creatine phosphokinase, deviation from the norm of biochemical indicators of liver function
Contraindications
Hypersensitivity to cabergoline or other components of the drug, as well as to any ergot alkaloids
Galactose intolerance
Lapp lactase deficiency
Glucose-galactose malabsorption
Hypertension during pregnancy, such as preeclampsia or postpartum hypertension
Severe psychotic or cognitive impairment (including history)
Pulmonary and heart failure caused by fibrotic changes or the presence of such conditions in history
Simultaneous use with drugs that have a hypotensive effect (due to the risk of developing orthostatic hypotension)
History of pulmonary heart disease associated with fibrosis (pulmonary, pericardial, and retroperitoneal fibrosis)
With long-term treatment, signs of cardiac valvulopathy according to echocardiography before treatment
kidney failure
Simultaneous reception with neuroleptics
Toxicosis of pregnant women
Children's age up to 16 years
Drug Interactions
Information on the interaction of cabergoline and other ergot alkaloids is not available, therefore, the simultaneous use of these drugs during long-term therapy with Dostinex® is not recommended.
Since Dostinex® has a therapeutic effect by direct stimulation of dopamine receptors, it cannot be administered simultaneously with drugs that act as dopamine antagonists (phenothiazines, butyrophenones, thioxanthenes, metoclopramide, etc.), because. they can weaken the action of Dostinex®, aimed at lowering prolactin levels.
Dostinex® should not be used simultaneously with macrolide antibiotics (for example, erythromycin), because. this may lead to an increase in the systemic bioavailability of cabergoline.
Dostinex® must be used with caution with drugs that lower blood pressure, because. the drug contributes to the development of symptomatic hypotension.
special instructions
Dostinex ® should be administered with caution in the following conditions and / or diseases:
Severe cardiovascular disease, Raynaud's syndrome
Peptic ulcer, gastrointestinal bleeding
Before using the drug, pregnancy must be excluded. After treatment with Dostinex®, pregnancy should be avoided for at least one month.
Dostinex needs to be used with caution ® with other drugs that lower blood pressure to avoid postural hypotension.
Before prescribing Dostinex ® in order to treat disorders associated with hyperprolactinemia, it is necessary to conduct a complete study of the function of the pituitary gland.
Before starting long-term drug treatment
Before starting long-term treatment, it is necessary to conduct examinations: echocardiography of the heart, chest x-ray, ultrasound of the kidneys, as well as blood and urine tests for the presence of an inflammatory process.
To identify possible asymptomatic valvular disease, all patients should undergo a cardiovascular examination, including echocardiography.
It is also advisable to determine the erythrocyte sedimentation rate (ESR) or the level of other markers of inflammation, evaluate lung function, perform a chest x-ray, and evaluate kidney function before starting treatment.
Data on a possible worsening of the course of the underlying disease in patients with valvular regurgitation are absent. If fibrosis of the heart valves is detected, cabergoline should not be prescribed.
During long-term treatment
Fibrotic changes can develop asymptomatically, so patients
should be monitored regularly to identify possible manifestations of progressive fibrosis.
Therefore, during treatment, it is necessary to pay attention to the signs and symptoms of the following conditions and diseases:
pleuropulmonary disease, which may present with dyspnea, shortness of breath, persistent cough or chest pain;
Renal insufficiency, obstruction of the ureters or vessels of the abdominal cavity, which may present with pain in the lumbar region or side and swelling of the lower extremities, as well as any masses or tenderness in the abdominal cavity, which may indicate retroperitoneal fibrosis;
heart failure, since valvular or pericardial fibrosis often presents with heart failure. Thus, when these symptoms appear, valvular fibrosis (and constrictive pericarditis) must be ruled out.
Proper clinical diagnostic monitoring is recommended to detect fibrotic changes. After the start of treatment, the first echocardiographic examination should be performed within 3–6 months; thereafter, the need for an echocardiographic examination should be determined by the results of a proper clinical examination on a case-by-case basis, with particular attention to the aforementioned signs and symptoms, but should be performed at least every 6 to 12 months.
If valvular regurgitation, restriction of mobility of the valve leaflets or their thickening is detected for the first time during echocardiography, as well as if signs of aggravation of the course of these conditions are detected, treatment with cabergoline should be discontinued.
The need for other methods of examination (for example, a clinical examination, including auscultation of the heart, X-ray examination and computed tomography) should be determined individually.
Additional laboratory tests, such as erythrocyte sedimentation rate (ESR) and serum creatinine, should be performed if necessary to confirm fibrotic changes.
In the case of an increase in ESR in the general blood test in patients with pleural effusion / fibrosis, it is necessary to conduct a chest x-ray.
Symptoms identified after long-term treatment with Dostinex®, such as fibrotic and serous inflammatory disorders (pleurisy, pleural effusion, pleural fibrosis, pulmonary fibrosis, pericarditis, pericardial effusion, heart failure), in some cases stop after discontinuation of the drug.
When increasing the dose, patients should be under the supervision of a physician in order to establish the lowest effective dose that provides a therapeutic effect.
Treatment of disorders caused by hyperprolactinemia
After an effective dosing regimen is selected, it is recommended to conduct regular (once a month) determination of the concentration of prolactin in the blood serum. Normalization of prolactin levels is usually observed within 2-4 weeks of treatment.
After discontinuation of Dostinex®, a relapse of hyperprolactinemia is usually observed, however, in some patients, persistent suppression of prolactin levels for several months is noted. In most women, ovulatory cycles persist for at least 6 months after discontinuation of Dostinex®.
Dostinex ® restores ovulation and fertility in women with hyperprolactinemic hypogonadism.
Since pregnancy can occur before the return of menstruation, it is recommended to carry out pregnancy tests at least once every 4 weeks during the amenorrhea period, and after the return of menstruation, every time there is a delay in menstruation by more than 3 days. Women who wish to avoid pregnancy should use barrier methods of contraception during treatment with Dostinex. ® , as well as after discontinuation of the drug until the recurrence of anovulation. Women who have become pregnant should be under the supervision of a doctor for the timely detection of symptoms of an enlarged pituitary gland, since during pregnancy an increase in the size of pre-existing pituitary tumors is possible.
Mental disorders
When using Dostinex ® Regular screening should be done to identify impulse control disorders that may present with behavioral symptoms such as gambling, increased libido, hypersexuality, compulsive spending or shopping, constant eating, and compulsive overeating. With the manifestation of such symptoms, it is necessary to reduce the dose and / or gradually discontinue the drug.
Liver failure
Patients with severe hepatic insufficiency (Child-Pugh class C) who are indicated for long-term therapy with Dostinex ® , you should consider taking the drug at lower doses. With a single dose of 1 mg in such patients, there was an increase in AUC (area under the concentration / time curve) compared with healthy volunteers and patients with less severe liver failure.
Fibrosis and cardiac valvulopathy
After long-term use of Dostinex®, patients have experienced pleural effusion/pleural fibrosis and valvulopathy. In some cases, patients have received prior therapy with ergoline dopamine agonists. Therefore, Dostinex® should be used with caution in patients with existing signs and / or clinical symptoms of cardiac dysfunction or with a history of such conditions. After stopping Dostinex ® in patients diagnosed with pleural effusion/pleural fibrosis and valvulopathy, there was an improvement in symptoms.
Studies to detect deterioration after taking Dostinex ® patients with valvular regurgitation were not performed. If the patient has fibrous valvular disorder, treatment with Dostinex ® Not recommended.
In patients with fibrotic disorders during long-term treatment with the drug, constant monitoring by a doctor is necessary for the timely diagnosis of an increase in symptoms of pleuropulmonary diseases, renal failure, ureteral or abdominal vascular obstruction, heart defects; and it is also necessary to regularly carry out additional research methods: general and biochemical blood tests (erythrocyte sedimentation rate, creatinine).
Drowsiness or sudden falling asleep
Application of Dostinex ® causes drowsiness, in patients with Parkinson's disease can cause sudden falling asleep. In such cases, it is recommended to reduce the dose of Dostinex ® or stop therapy.
Studies on the use of the drug in elderly patients with
disorders associated with hyperprolactinemia were not performed.
Application in pediatrics
The safety and efficacy of the drug in children under 16 years of age has not been established.
Pregnancy and lactation
Since no controlled clinical studies have been conducted with the use of Dostinex® in pregnant women, the drug should be discontinued during pregnancy.
Pregnancy should be avoided for at least one month after discontinuation of Dostinex, given the long half-life of the drug and the limited data on its effect on the fetus (although, according to available data, the use of Dostinex at a dose of 0.5 - 2 mg per week for disorders associated with hyperprolactinemia was not accompanied by an increase in the frequency of miscarriages, premature births, multiple pregnancies and congenital malformations).
There is no information on the excretion of the drug with breast milk, however, in the absence of the effect of using Dostinex® to prevent or suppress lactation, mothers should stop breastfeeding. For disorders associated with hyperprolactinemia, Dostinex® should not be administered to mothers who wish to breastfeed.
During lactation, a single dose of Dostinex® should not exceed 0.25 mg, in order to avoid manifestations of hypotension. Clinical studies have shown that with a single dose of the drug 0.5 mg to suppress lactation, the risk of side effects doubles.
Features of the effect of the drug on the ability to drive a vehicle and other potentially dangerous mechanisms
Patients taking Dostinex ® Persons who experience drowsiness should be warned that they are advised to refrain from driving and from performing work (such as operating machinery) in which reduced alertness could put them or others at risk of serious injury or death.
- Instructions for use Dostinex
- Ingredients of Dostinex
- Indications for Dostinex
- Storage conditions of the drug Dostinex
- Shelf life of the drug Dostinex
Release form, composition and packaging
tab. 500 mcg: 2 or 8 pcs.Reg. No: 1110/97/03/07/12 dated 11/01/2012 - Valid
Pills white, flat, oblong; on one side the inscription "PU" is engraved, divided by a notch; the other side is engraved with the inscription "700" and light notches above and below the central "0".
Excipients: anhydrous lactose, leucine (E641).
2 pcs. - dark glass bottles (1) - cardboard boxes.
8 pcs. - dark glass bottles (1) - cardboard boxes.
Description of the medicinal product DOSTINEX based on the officially approved instructions for use of the drug and made in 2013. Date of update: 02/27/2013
Dostinex is a dopaminergic ergoline derivative with a pronounced and long-lasting prolactin-lowering activity. Its mechanism of action is associated with direct stimulation of dopamine D 2 -receptors of lactotropic pituitary cells, which leads to a decrease in prolactin secretion. This compound reduces prolactin secretion in rats at an oral dose of 3-25 μg/kg, and in vitro at a concentration of 45 pg/ml. In addition, cabergoline has a central dopaminergic effect due to stimulation of dopamine D 2 receptors when administered orally at doses higher than those required to reduce plasma prolactin levels. The long-term prolactin-lowering effect of cabergoline is probably due to its long residence time in the target organ, as suggested by the slow elimination of total radioactivity from the pituitary after a single oral dose in rats (T 1/2 is approximately 60 hours). The pharmacodynamic effects of cabergoline have been studied in healthy volunteers, postpartum women and patients with hyperprolactinemia. After a single oral dose of cabergoline (at a dose of 0.3-1.5 mg), a significant decrease in serum prolactin levels was observed in each of the studied groups. This effect develops quickly (within 3 hours after administration) and persists for a long time (up to 7-28 days in healthy volunteers and patients with hyperprolactinemia and up to 14-21 days in women in the postpartum period). The prolactin-lowering effect is dose-dependent both in terms of severity and duration of effect. With regard to the endocrine effects of cabergoline, not related to its antiprolactinemic action, the data obtained in humans confirm the experimental data obtained in animals and indicate that the test substance has a highly selective effect and does not affect the basal secretion of other pituitary hormones or cortisol. The pharmacodynamic profile of cabergoline did not correlate with the therapeutic effect only in terms of lowering blood pressure. The maximum hypotensive effect of cabergoline with a single dose usually develops within the first 6 hours after taking the drug and is dose-dependent both in terms of the maximum reduction in blood pressure and in terms of the frequency of the effect.
Suction
The pharmacokinetic and metabolic profiles of cabergoline were studied in healthy volunteers of both sexes and in female patients with hyperprolactinemia.
After oral administration of the labeled compound, radioactivity was rapidly absorbed from the gastrointestinal tract, with peak plasma radioactivity reaching between 0.5 and 4 hours.
Ten days after ingestion of the compound, about 18% and 72% of the administered radioactive dose was excreted in the urine and feces, respectively. The amount of unchanged drug in the urine was 2-3% of the administered dose.
Eating does not affect the absorption and distribution of cabergoline.
Distribution
In vitro experiments have shown that cabergoline at a concentration of 0.1-10 ng/ml binds to plasma proteins by 41-42%.
Metabolism
The main metabolite identified in urine was 6-allyl-8p-carboxy-ergoline, amounting to 4-6% of the administered dose. Three other metabolites were identified in urine, the total content of which was less than 3% of the administered dose. The metabolites have been found to have a much less pronounced inhibitory effect on prolactin secretion in vitro than cabergoline. The biotransformation of cabergoline has also been studied in the plasma of healthy male volunteers treated with [ 14 C]-cabergoline:
- fast and extensive biotransformation of cabergoline was found.
breeding
The low level of excretion of unchanged cabergoline in the urine was also confirmed in studies using a non-radioactive drug. According to the results of urinary excretion, cabergoline has a long half-life (63-68 hours in healthy volunteers using radioimmunoassay, 79-115 hours in patients with hyperprolactinemia using HPLC). Considering T 1/2 , steady state can be achieved after 4 weeks of dosing, which was confirmed by mean plasma Cmax levels of cabergoline obtained after a single dose (37 ± 8 pg/mL) and after a 4-week multiple dose (101 ±43 pg/ml).
Inhibition/suppression of physiological lactation:
- to inhibit physiological lactation shortly after childbirth;
- to suppress already established lactation (after childbirth, when the mother decides to refuse breastfeeding of the child, or in cases where breastfeeding is contraindicated for the mother or child for medical reasons; after a miscarriage or abortion).
- for the treatment of disorders associated with hyperprolactinemia, including such functional disorders as amenorrhea, oligomenorrhea, anovulation and galactorrhea;
- prolactin-secreting pituitary adenomas (micro- and macroprolactinomas), idiopathic hyperprolactinemia or "empty" sella syndrome in combination with hyperprolactinemia, which are the main types of pathology leading to the development of the above-mentioned clinical manifestations.
Treatment of disorders associated with hyperprolactinemia:
Tablets should be taken orally. Since the tolerability of dopaminergic drugs improves when taken with food, it is recommended that Dostinex be taken with meals.
In patients with a history of intolerance to dopaminergic agents, the likelihood of developing adverse events can be reduced by starting cabergoline therapy at lower doses (eg, 0.25 mg once a week) followed by a gradual increase in dosage until a therapeutic dose is reached. In the event of persistent or severe adverse events, tolerability can be improved by temporarily reducing the dose followed by a gradual increase (for example, an increase of 0.25 mg per week every two weeks).
For suppression of established lactation the recommended dosage is 0.25 mg (half a 0.5 mg tablet) every 12 hours for 2 days (total dose 1 mg).
The recommended starting dose of cabergoline is 0.5 mg per week in 1 or 2 doses (1/2 tab. 0.5 mg) during the week (for example, on Monday and Thursday). Increasing the weekly dose should be carried out gradually, preferably by 0.5 mg per week with an interval of 1 month until the optimal therapeutic effect is achieved. The therapeutic dose is usually 1 mg per week, but may range from 0.25 mg to 2 mg per week. In patients with hyperprolactinemia, doses up to 4.5 mg per week have been used.
The weekly dose may be administered in 1 dose or divided into 2 or more doses per week, depending on patient tolerance. When prescribing the drug in doses exceeding 1 mg per week, it is recommended to divide the weekly dose into several doses.
Patients should be evaluated during dose escalation to determine the lowest effective dose that produces a therapeutic effect. After reaching a therapeutic dose, monthly regular determination of the level of prolactin in the blood serum is recommended. Normalization of serum prolactin levels is usually observed within 2 to 4 weeks of treatment.
After discontinuation of cabergoline, a relapse of hyperprolactinemia is usually observed. However, a number of patients experienced persistent suppression of prolactin levels for several months. In most women, ovulatory cycles persist for at least 6 months after cabergoline is discontinued.
Patients with severe liver failure lower doses of cabergoline should be given.
The safety and efficacy of the drug in patients under the age of 16 not installed.
Official studies on the use of cabergoline in the elderly for the treatment of disorders associated with hyperprolactinemia have not been performed.
Adverse reactions reported with cabergoline are listed below by MedDRA organ system class and frequency, which was determined as follows:
- very often (>1/10), often (>1/100 to<1/10), нечасто (от >1/1000 to<1/100), редко (от >1/10,000 to 1/1000), very rare (<1/10 000), частота неизвестна (не может быть установлена на основании доступных данных).
general information
often - in patients receiving long-term treatment, cabergoline usually has a hypotensive effect;
From the musculoskeletal system: infrequently - convulsive twitching of the muscles of the legs.
From the hematopoietic system: infrequently - a decrease in hemoglobin levels has been reported in women with amenorrhea during the first few months after the resumption of menstruation.
Disorders associated with hyperprolactinemia
From the side of the psyche: often - depression, sleep disturbances;
From the nervous system: very often - dizziness / vertigo, headache;
From the side of the cardiovascular system: often hot flashes.
From the gastrointestinal tract: very often - abdominal pain, dyspepsia, gastritis, nausea;
From the genitals and mammary gland: often - pain in the mammary glands.
Others: very often - asthenia / weakness.
Inhibition/suppression of lactation
From the nervous system: very often - dizziness / vertigo, headache, drowsiness;
From the side of the cardiovascular system: very often - valvulopathy (including regurgitation) and concomitant diseases of the disease (pericarditis and pericardial effusion);
infrequently - epistaxis, pleural effusion, pulmonary fibrosis.
From the gastrointestinal tract: often - abdominal pain, nausea;
From the side of the organ of vision: frequency unknown - abnormal vision.
Others: very often - asthenia.
Post-marketing surveillance
From the immune system: frequency unknown - hypersensitivity reactions.
From the side of the psyche: frequency unknown - delirium, mental disorder.
From the respiratory system: infrequently - shortness of breath;
From the side of the liver and biliary tract: the frequency is unknown - abnormal liver function.
From the skin and subcutaneous tissues: infrequently - alopecia, rash.
Others: infrequently - edema, an increase in the level of CPK, violations of laboratory parameters of liver function.
- a history of pulmonary, pericardial and retroperitoneal fibrotic changes;
- hypersensitivity to cabergoline, other components of the drug or any ergot alkaloids.
- anatomical signs of valvulopathy of any heart valve, identified before treatment with cabergoline by echocardiography (thickening of the valve leaflets, valve narrowing, combined stenosis - valve narrowing).
Long-term use of the drug
Use during pregnancy and lactation
Animal studies of cabergoline have not shown any teratogenic effects or effects on overall fertility. However, there are no adequate and well-controlled studies in pregnant women. Cabergoline should only be used during pregnancy if absolutely necessary. If conception occurs during treatment with cabergoline, consideration should be given to discontinuing treatment after a careful assessment of the risks and benefits to the mother and fetus. Pregnancy should be avoided for at least 1 month after discontinuation of cabergoline treatment, as it has a long half-life and there are only limited data on the effect of the drug on the fetus, although the use of cabergoline at a dose of 0.5 to 2 mg per week in the treatment of disorders associated with hyperprolactinemia, is not accompanied by an increased risk of miscarriage, premature birth, multiple pregnancy or congenital malformations of the fetus.
In rats, cabergoline and/or its metabolites are excreted in milk. No information is available on excretion in human milk; however, mothers should be advised not to breastfeed if cabergoline has failed to inhibit/suppress lactation. Since the drug suppresses lactation, cabergoline should not be administered to mothers with disorders associated with hyperprolactinemia who wish to breastfeed their children.
As with other ergot derivatives, cabergoline should be used with caution in patients with severe cardiovascular disease, Raynaud's syndrome, peptic ulcer or gastrointestinal bleeding, and in patients with a history of severe psychiatric illness, especially psychosis.
Liver failure
In long-term treatment of patients with severe hepatic insufficiency, cabergoline should be administered at lower doses. In patients with severe hepatic insufficiency (Child-Pugh C) who took a single dose of 1 mg, an increase in AUC was observed when compared with healthy volunteers and individuals with lesser hepatic insufficiency.
orthostatic hypotension
After taking cabergoline, orthostatic hypotension may develop. Against the background of therapy with drugs that have an antihypertensive effect, cabergoline should be administered with caution.
Fibrosis/Valvulopathy
As with other ergot derivatives, cases of pleural effusion/pneumofibrosis and valvulopathy have been reported with long-term administration of cabergoline. Several of these reports have been in patients previously treated with ergoline dopamine receptor agonists. Therefore, in patients with a history or present of signs and/or clinical symptoms characteristic of respiratory or cardiac disorders associated with the formation of fibrous tissue, cabergoline should be used with caution. With the development of pleural effusion/fibrosis, an increase in ESR was recorded. In the case of an unexplained increase in ESR above normal, an X-ray examination of the chest organs is recommended. Plasma creatinine can also be used to facilitate the diagnosis of fibrotic changes. Discontinuation of cabergoline after diagnosis of pleural effusion/pneumofibrosis or valvulopathy has been reported to improve signs and symptoms of the disease.
Long-term use of the drug
Before starting long-term use of the drug: all patients should have a cardiovascular assessment, including echocardiography, to determine the presence of asymptomatic valvular heart disease. Baseline determinations of erythrocyte sedimentation rate or other markers of inflammation, lung function/radiography, and renal function should also be performed prior to initiation of treatment. It is not known whether taking cabergoline in patients with valvular regurgitation can worsen the course of the underlying disease. In the case of diagnosing fibrotic changes in the heart valves, patients should not be treated with cabergoline.
During long-term use of the drug: fibrotic changes may be asymptomatic; it is necessary to regularly monitor the condition of patients for possible manifestations of progressive fibrosis. Therefore, during treatment it is necessary to pay attention to signs and symptoms:
- pleuropulmonary pathology such as dyspnea, shortness of breath, persistent cough or chest pain;
- renal failure or ureteral/abdominal vascular occlusion, which may present with pain in the lumbar region/sides of the body and swelling of the lower extremities, and possibly abdominal masses or tenderness, which may indicate retroperitoneal fibrosis;
- Heart failure: Cases of valvular or pericardial fibrosis often manifested as heart failure. Therefore, valvular fibrosis (and constrictive pericarditis) should be ruled out when these symptoms appear.
Of great importance is the proper clinical diagnostic control for the development of fibrotic changes. After the start of treatment, the first echocardiography should be completed within 3-6 months; thereafter, the frequency of follow-up echocardiography should be determined according to appropriate individual clinical judgment, with particular reference to the aforementioned signs and symptoms, and should be performed at least every 6 to 12 months.
If the echocardiogram reveals new signs or there is a negative trend in valvular regurgitation, restriction of the mobility of the valve leaflets or thickening of the valve leaflets, treatment with cabergoline should be discontinued.
The need for other clinical controls (eg, physical examination including cardiac auscultation, x-ray, computed tomography) should be determined on an individual basis.
Additional appropriate laboratory tests, such as erythrocyte sedimentation rate and plasma creatinine determination, should be performed if necessary to confirm the diagnosis of fibrotic changes.
Drowsiness/Sudden onset of sleep
The appointment of cabergoline was associated with the development of drowsiness. The administration of dopamine receptor agonists may be associated with episodes of sudden onset of sleep in patients with Parkinson's disease. In this case, you should reduce the dose or stop treatment with the drug.
Inhibition/suppression of physiological lactation
As with other ergot derivatives, cabergoline should not be used in women with pregnancy-related hypertension, such as preeclampsia or postpartum hypertension, unless the potential benefit outweighs the risk.
It is not recommended to exceed a single dose of cabergoline equal to 0.25 mg in nursing mothers during treatment aimed at suppressing already established lactation, in order to prevent the possible development of orthostatic hypotension.
Treatment of disorders associated with hyperprolactinemia
Before starting treatment with cabergoline, a complete examination of the pituitary gland is indicated.
Cabergoline restores ovulation and fertility in women with hyperprolactinemic hypogonadism. Since pregnancy can occur even before the restoration of menstruation, it is recommended to conduct pregnancy tests at least 1 time in 4 weeks during the amenorrhea period, and after the restoration of menstruation, every time there is a delay in menstruation by more than 3 days. Women who wish to avoid pregnancy should be advised to use mechanical methods of contraception during and after cabergoline treatment until anovulation returns. Women who have become pregnant should be under the supervision of a doctor as a precaution, for the timely detection of symptoms of an enlarged pituitary gland, since during pregnancy an increase in the size of pre-existing pituitary tumors is possible.
Psychiatric disorders
There are reports of cases of pathological excitement, increased sexual desire and hypersexuality in patients taking dopamine agonists, including cabergoline. These events were generally reversible with dose reduction or drug withdrawal.
Influence on the ability to drive a car and control mechanisms
Patients receiving cabergoline treatment who experience drowsiness should be instructed to refrain from driving or engaging in activities where impaired alertness could result in a risk of serious injury or death to themselves or others (eg, operating machinery) until until they stop feeling so sleepy.
Preclinical safety data
Virtually all data from a series of preclinical safety studies are due to central dopaminergic effects or long-term suppression of prolactin secretion in species with a specific hormonal physiology different from that of humans (rodents). Preclinical studies of cabergoline indicate a wide range of safety of this compound in rodents and monkeys, as well as the absence of teratogenic, mutagenic and carcinogenic potential.
Symptoms: nausea, vomiting, dyspeptic disorders, orthostatic hypotension, confusion/psychosis or hallucinations.
Treatment: measures should be taken to eliminate the drug (gastric lavage) and to maintain blood pressure. The appointment of dopamine antagonists is recommended.
Information on the interaction of cabergoline and other ergot alkaloids is not available; however, concomitant use of these medicinal products during long-term cabergoline therapy is not recommended.
Since cabergoline exerts its therapeutic effect through direct stimulation of dopamine receptors, it should not be administered simultaneously with drugs with dopamine antagonistic activity (such as derivatives of phenothiazine, butyrophenone, thioxanthene, metoclopramide), because. this may weaken the prolactin-lowering effect of cabergoline.
As with other ergot derivatives, cabergoline should not be co-administered with macrolide antibiotics (eg, erythromycin), as this may increase the systemic bioavailability of cabergoline.
PFIZER EXPORT B.V., representative office, (Kingdom of the Netherlands)
Representation Hprivate limited companyPfizer Export B.V." in the Republic of Belarus
Dopamine receptor agonist. Cabergoline is a dopaminergic derivative of ergoline, characterized by a pronounced and prolonged prolactin-lowering effect. The mechanism of action is associated with direct stimulation of dopamine D 2 receptors of lactotropic pituitary cells. In doses exceeding those to reduce plasma prolactin levels, it has a central dopaminergic effect due to stimulation of dopamine D 2 receptors.
A decrease in the level of prolactin in the blood plasma is observed 3 hours after taking Dostinex and persists for 7-28 days in healthy volunteers and patients with hyperprolactinemia and up to 14-21 days in women in the postpartum period. The prolactin-lowering effect is dose-dependent both in terms of severity and duration of action.
Cabergoline has a highly selective effect and, therefore, does not affect the basal secretion of other pituitary hormones, as well as cortisol.
The pharmacological effects of cabergoline, not associated with a therapeutic effect, include a decrease in blood pressure. With a single use of the drug, the maximum hypotensive effect is observed during the first 6 hours and is dose-dependent.
Pharmacokinetics
Suction
After oral administration, cabergoline is rapidly absorbed from the gastrointestinal tract. C max in plasma is reached in 0.5-4 hours. Food intake does not affect the absorption and distribution of cabergoline.
Distribution
C ss achieved after 4 weeks of therapy due to long T 1/2 . Plasma protein binding is 41-42%.
Metabolism
The main product of cabergoline metabolism identified in urine is 6-allyl-8β-carboxy-ergoline at concentrations up to 4-6% of the administered dose. The content in the urine of 3 additional metabolites does not exceed 3% of the dose taken. Metabolic products have a significantly lower effect on the suppression of prolactin secretion compared to cabergoline.
breeding
T 1/2 estimated by the rate of excretion in the urine is 63-68 hours in healthy volunteers and 79-115 hours in patients with hyperprolactinemia.
10 days after the use of the drug in the urine and feces, 18% and 72% of the dose taken, respectively, are found, and the proportion of unchanged drug in the urine is 2-3%.
Release form
Tablets are white, flat, oblong; marked "P" and "U", separated by a notch, on the one hand, and "700" with short notches above and below the number, on the other.
Excipients: anhydrous lactose - 75.9 mg, leucine - 3.6 mg.
2 pcs. - dark glass bottles (1) - packs of cardboard.
8 pcs. - dark glass bottles (1) - packs of cardboard.
Dosage
Dostinex ® should be taken orally, preferably with food.
To prevent lactation, the drug is prescribed at a dose of 1 mg (2 tablets) once on the first day after childbirth.
To suppress established lactation, 0.25 mg (1/2 tab.) is prescribed 2 times / day for 2 days (total dose is 1 mg). In order to reduce the risk of developing orthostatic hypotension in lactating patients, a single dose of Dostinex should not exceed 0.25 mg.
For the treatment of disorders associated with hyperprolactinemia, the drug is prescribed at a dose of 0.5 mg per week in 1 (1 tab.) or 2 doses (1/2 tab., for example, on Monday and Thursday). Increasing the weekly dose should be carried out gradually - by 0.5 mg with an interval of 1 month until the optimal therapeutic effect is achieved. The average therapeutic dose is 1 mg per week, but can range from 0.25 mg to 2 mg per week. The maximum dose for patients with hyperprolactinemia is 4.5 mg per week.
Depending on tolerance, the weekly dose can be taken once or divided into 2 or more doses per week. Dividing the weekly dose into several doses is recommended when prescribing the drug at a dose of more than 1 g per week.
In patients with hypersensitivity to dopaminergic drugs, the likelihood of developing side effects can be reduced by starting Dostinex therapy at a lower dose (0.25 mg once a week), followed by a gradual increase until the therapeutic dose is reached. To improve the tolerability of the drug in the event of severe side effects, a temporary dose reduction is possible, followed by a gradual increase, for example, by 0.25 mg per week every 2 weeks.
Overdose
Symptoms: nausea, vomiting, dyspeptic disorders, orthostatic hypotension, confusion/psychosis or hallucinations.
Treatment: measures should be taken to eliminate the drug (gastric lavage) and to maintain blood pressure. The appointment of dopamine antagonists is recommended.
Interaction
There is no information on the interaction of cabergoline and other ergot alkaloids; however, the concomitant use of these medicinal products during long-term therapy with Dostinex is not recommended.
Since Dostinex ® has a therapeutic effect by direct stimulation of dopamine receptors, the drug should not be administered simultaneously with drugs that act as dopamine antagonists (for example, phenothiazines, butyrophenones, thioxanthenes, metoclopramide), because. the latter may weaken the prolactin-lowering effect of Dostinex.
Like other ergot derivatives, Dostinex ® should not be used simultaneously with macrolide antibiotics (eg erythromycin), as this may lead to an increase in the systemic bioavailability of cabergoline.
Side effects
In clinical studies using Dostinex to prevent physiological lactation (1 mg once) and to suppress lactation (0.25 mg every 12 hours for 2 days), side effects were observed in approximately 14% of women. When using Dostinex for 6 months at a dose of 1-2 mg per week, divided into 2 doses, for the treatment of disorders associated with hyperprolactinemia, the incidence of side effects was 68%. Side effects occurred mainly during the first 2 weeks of therapy and in most cases disappeared as therapy continued or a few days after Dostinex was discontinued. Side effects were usually transient, mild or moderate in severity and were dose-dependent. At least once, during therapy, severe side effects were observed in 14% of patients; due to side effects, treatment was discontinued in approximately 3% of patients.
The most common side effects are listed below:
From the side of the cardiovascular system: palpitations; rarely - orthostatic hypotension (with prolonged use, the drug has a hypotensive effect); asymptomatic decrease in blood pressure during the first 3-4 days after delivery (systolic - more than 20 mm Hg, diastolic - more than 10 mm Hg).
From the digestive system: nausea, vomiting, epigastric pain, abdominal pain, constipation, gastritis, dyspepsia.
From the side of the central nervous system and peripheral nervous system: dizziness / vertigo, headache, fatigue, drowsiness, depression, asthenia, paresthesia, fainting.
Others: mastodynia, epistaxis, flushing of the skin of the face, transient hemianopsia, spasms of the vessels of the fingers, muscle spasms of the lower extremities (like other ergot derivatives, Dostinex ® may have a vasoconstrictive effect).
With long-term therapy with the use of Dostinex, a deviation from the norm of standard laboratory parameters was rarely observed; in women with amenorrhea, a decrease in hemoglobin levels was observed during the first few months after the restoration of menstruation.
In a post-marketing study, the following adverse reactions associated with the use of cabergoline were registered: alopecia, increased CPK activity in the blood, mania, dyspnea, edema, fibrosis, abnormal liver function, abnormal liver function tests, hypersensitivity reactions, rash, respiratory disorders, respiratory failure, valvulopathy.
Indications
- prevention of physiological postpartum lactation;
- suppression of established postpartum lactation;
- treatment of disorders associated with hyperprolactinemia, including amenorrhea, oligomenorrhea, anovulation and galactorrhea;
- prolactin-secreting pituitary adenomas (micro- and macroprolactinomas), idiopathic hyperprolactinemia, empty sella syndrome in combination with hyperprolactinemia.
Contraindications
- children and adolescents under 16 years of age (safety and effectiveness of use have not been established);
- hypersensitivity to cabergoline or other components of the drug, as well as to any ergot alkaloids.
Dostinex ® should be administered with caution in the following conditions and / or diseases:
- arterial hypertension that developed during pregnancy, for example, preeclampsia or postpartum arterial hypertension (Dostinex ® is prescribed only in cases where the potential benefit of using the drug significantly outweighs the possible risk);
- severe cardiovascular disease, Raynaud's syndrome;
- peptic ulcer, gastrointestinal bleeding;
- severe liver failure (lower doses are recommended);
- severe psychotic or cognitive impairment (including history);
- symptoms of dysfunction of the heart and breathing due to fibrotic changes or the presence of such conditions in history;
- simultaneous use with drugs that have a hypotensive effect (due to the risk of developing orthostatic hypotension).
Application features
Use during pregnancy and lactation
Since no controlled clinical trials have been conducted with the use of Dostinex in pregnant women, the use of the drug during pregnancy is possible only if the intended benefit to the mother outweighs the potential risk to the fetus.
If pregnancy occurs during treatment with Dostinex, the advisability of discontinuing the drug should be considered, also taking into account the benefit / risk ratio.
Pregnancy should be avoided for at least 1 month after discontinuation of the drug, given its long half-life and limited data on effects on the fetus. According to available data, the use of Dostinex at a dose of 0.5-2 mg per week for disorders associated with hyperprolactinemia was not accompanied by an increase in the frequency of miscarriages, premature births, multiple pregnancies and congenital malformations.
There is no information on the release of the drug with breast milk, however, in the absence of the effect of using Dostinex to prevent or suppress lactation, breastfeeding should be abandoned. For disorders associated with hyperprolactinemia, Dostinex ® should not be prescribed to mothers who do not want to stop lactation.
Application for violations of liver function
The drug is used with caution in severe liver failure (lower doses are recommended).Use in children
Contraindication: children and adolescents under 16 years of age (safety and efficacy have not been established).special instructions
Before the appointment of Dostinex for the treatment of disorders associated with hyperprolactinemia, it is necessary to conduct a complete study of the function of the pituitary gland.
When increasing the dose, patients should be under the supervision of a physician in order to establish the lowest effective dose that provides a therapeutic effect. After an effective dosing regimen is selected, it is recommended to conduct regular (once a month) determination of the concentration of prolactin in the blood serum. Normalization of prolactin levels is usually observed within 2-4 weeks of treatment.
After discontinuation of Dostinex, a recurrence of hyperprolactinemia is usually observed, however, in some patients, persistent suppression of prolactin levels is noted for several months. In most women, ovulatory cycles persist for at least 6 months after discontinuation of Dostinex.
Dostinex ® restores ovulation and fertility in women with hyperprolactinemic hypogonadism. Since pregnancy can occur before the return of menstruation, it is recommended to carry out pregnancy tests at least once every 4 weeks during the amenorrhea period, and after the return of menstruation, every time there is a delay in menstruation by more than 3 days. Women who wish to avoid pregnancy should use barrier methods of contraception during treatment with Dostinex, as well as after discontinuation of the drug until anovulation is repeated. Women who have become pregnant should be under the supervision of a doctor for the timely detection of symptoms of an enlarged pituitary gland, since during pregnancy an increase in the size of pre-existing pituitary tumors is possible.
Dostinex ® should be administered at lower doses to patients with severe hepatic impairment (Child-Pugh class C) who are indicated for long-term drug therapy. With a single dose of 1 mg to such patients, an increase in AUC was observed compared with healthy volunteers and patients with less severe liver failure.
As with other ergot derivatives, pleural effusion/pleural fibrosis and valvulopathy have been observed in patients after long-term cabergoline use. In some cases, patients have received prior therapy with ergothinine dopamine agonists. Therefore, Dostinex ® should be used with caution in patients with existing signs and / or clinical symptoms of cardiac dysfunction or with a history of such conditions. After discontinuation of Dostinex in patients diagnosed with pleural effusion/pleural fibrosis and valvulopathy, there was an improvement in symptoms.
The use of cabergoline causes drowsiness. In patients with Parkinson's disease, the use of dopamine receptor agonists can cause sudden sleep. In such cases, it is recommended to reduce the dose of Dostinex or stop therapy.
Studies on the use of the drug in elderly patients with disorders associated with hyperprolactinemia have not been conducted.
Pediatric use
The safety and efficacy of the drug in children under 16 years of age has not been established.
Influence on the ability to drive vehicles and control mechanisms
Patients taking Dostinex ® who experience drowsiness should be warned that they are advised to refrain from driving a car and from performing work (for example, with machinery) in which reduced attention could put them or others at risk of serious injury or of death.
Compound
Description of the dosage form
White flat oblong tablets marked "P" and "U", separated by a notch on one side and "700" with short notches above and below the number on the other side.
pharmachologic effect
pharmachologic effect- dopaminomimetic, hypoprolactinemic.Pharmacodynamics
Cabergoline is a dopaminergic derivative of ergoline and is characterized by a pronounced and prolonged prolactin-lowering effect due to direct stimulation of D 2 -dopamine receptors of lactotropic pituitary cells. In addition, when taken at higher doses compared to doses to reduce serum prolactin levels, cabergoline has a central dopaminergic effect due to stimulation of D 2 receptors.
A decrease in the concentration of prolactin in the blood plasma is noted within 3 hours after taking the drug and persists for 7-28 days in healthy volunteers and patients with hyperprolactinemia and up to 14-21 days in women in the postpartum period.
Cabergoline has a strictly selective effect, does not affect the basal secretion of other pituitary hormones and cortisol. The prolactin-lowering effect of the drug is dose-dependent, both in terms of severity and duration of action.
The pharmacodynamic effects of cabergoline, not associated with a therapeutic effect, include only a decrease in blood pressure. With a single dose of the drug, the maximum hypotensive effect is observed during the first 6 hours and is dose-dependent.
Pharmacokinetics
Cabergoline is rapidly absorbed from the gastrointestinal tract, Cmax in plasma is reached after 0.5-4 hours, the relationship with plasma proteins is 41-42%. T 1/2 cabergoline, estimated by the rate of excretion by the kidneys, is 63-68 hours in healthy volunteers and 79-115 hours in patients with hyperprolactinemia. Due to the long T 1/2 , C ss is reached after 4 weeks . 10 days after taking the drug in the urine and feces, about 18 and 72% of the dose taken, respectively, are found, and the proportion of unchanged drug in the urine is 2-3%. The main product of cabergoline metabolism identified in urine is 6-allyl-8β-carboxy-ergoline at concentrations up to 4-6% of the administered dose. The content in the urine of 3 additional metabolites does not exceed 3% of the dose taken. Metabolic products have been found to have a significantly lesser effect on suppressing prolactin secretion compared to cabergoline.
Eating does not affect the absorption and distribution of cabergoline.
Indications for Dostinex ®
prevention of physiological lactation after childbirth;
suppression of already established postpartum lactation;
treatment of disorders associated with hyperprolactinemia, including amenorrhea, oligomenorrhea, anovulation, galactorrhea;
prolactin-secreting pituitary adenomas (micro- and macroprolactinomas); idiopathic hyperprolactinemia; syndrome of an empty Turkish saddle in combination with hyperprolactinemia.
Contraindications
hypersensitivity to cabergoline or other components of the drug, as well as any ergot alkaloids;
violations of the function of the heart and breathing due to fibrotic changes or the presence of such conditions in history;
with long-term therapy: anatomical signs of pathology of the valvular apparatus of the heart (such as thickening of the valve leaflet, narrowing of the valve lumen, mixed pathology - narrowing and stenosis of the valve), confirmed by an echocardiographic study (EchoCG) conducted before the start of therapy;
lactose intolerance, lactase deficiency, glucose-galactose malabsorption;
use in children and adolescents under the age of 16 years (safety and efficacy of the drug have not been established).
Carefully
Like other ergot derivatives, Dostinex ® should be prescribed with caution in the following conditions and / or diseases: arterial hypertension that developed during pregnancy, such as preeclampsia or postpartum arterial hypertension (Dostinex ® is prescribed only in cases where the potential benefit from the use of the drug is significant outweighs the risk). severe cardiovascular disease, Raynaud's syndrome; peptic ulcer, gastrointestinal bleeding; severe liver failure (lower doses are recommended); severe psychotic or cognitive impairment (including history); simultaneous use with drugs that have a hypotensive effect (due to the risk of developing orthostatic arterial hypotension).
Use during pregnancy and lactation
Since controlled clinical trials with the use of Dostinex ® in pregnant women have not been conducted, the appointment of the drug during pregnancy is possible only in cases of emergency, taking into account the benefit / risk ratio for the woman and the fetus.
If pregnancy occurs during treatment with Dostinex ® , the expediency of discontinuing the drug should be considered, also taking into account the benefit / risk ratio.
According to available data, the use of the drug Dostinex ® at a dose of 0.5-2 mg per week for disorders associated with hyperprolactinemia was not accompanied by an increase in the frequency of miscarriages, premature births, multiple pregnancies and congenital malformations.
There is no information on the excretion of the drug with breast milk, however, in the absence of the effect of using Dostinex ® to prevent or suppress lactation, mothers should stop breastfeeding. With disorders associated with hyperprolactinemia, Dostinex ® is contraindicated in patients planning to breastfeed.
Side effects
In clinical studies using Dostinex ® to prevent physiological lactation (1 mg once) and to suppress lactation (0.25 mg every 12 hours for 2 days), side effects were observed in approximately 14% of women. When using Dostinex ® for 6 months at a dose of 1-2 mg / week, divided into 2 doses, for the treatment of disorders associated with hyperprolactinemia, the incidence of side effects was 68%. Side effects occurred mainly during the first 2 weeks of therapy and in most cases disappeared as therapy continued or a few days after Dostinex was discontinued. Side effects were usually transient, mild or moderate in severity, and were dose-dependent. At least once during therapy, severe side effects were observed in 14% of patients; due to side effects, treatment was discontinued in approximately 3% of patients.
The most common side effects are listed below.
From the CCC: feeling of heartbeat; rarely - orthostatic hypotension (with prolonged use, Dostinex ® usually has a hypotensive effect); an asymptomatic decrease in blood pressure is possible during the first 3-4 days after delivery (SBP - not less than 20 mm Hg, diastolic blood pressure - not less than 10 mm Hg).
From the nervous system: dizziness / vertigo, headache, fatigue, drowsiness, depression, asthenia, paresthesia, fainting, nervousness, anxiety, insomnia, impaired concentration.
From the digestive system: nausea, vomiting, pain in the epigastric region, abdominal pain, constipation, gastritis, dyspepsia, dryness of the oral mucosa, diarrhea, flatulence, toothache, irritation of the pharyngeal mucosa.
Others: mastodynia, dysmenorrhea, epistaxis, rhinitis, flushing of the face, transient hemianopsia, spasms of the digital vessels and muscle spasms of the lower extremities (like other ergot derivatives, Dostinex ® may have a vasoconstrictive effect), visual impairment, flu-like symptoms, malaise, periorbital and peripheral edema, anorexia, acne, pruritus, joint pain.
With long-term therapy with the use of the drug Dostinex ®, a deviation from the norm of standard laboratory parameters was rarely observed; in women with amenorrhea, a decrease in Hb levels was observed during the first few months after the restoration of menstruation.
In a post-marketing study, the following side effects associated with cabergoline were also registered: alopecia, increased CPK activity in the blood, mania, dyspnea, edema, fibrosis, abnormal liver function and abnormal liver function tests, hypersensitivity reactions, rash, respiratory disorders, respiratory failure , valvulopathy, pathological gambling, hypersexuality, increased libido, aggressiveness, psychotic disorders, pericarditis, sudden sleep attacks, weight loss or increase, nasal congestion.
Interaction
Information on the interaction of cabergoline and other ergot alkaloids is not available, therefore, the simultaneous use of these drugs during long-term therapy with Dostinex ® is not recommended.
Since cabergoline has a therapeutic effect by direct stimulation of dopamine receptors, it cannot be administered simultaneously with drugs that act as dopamine antagonists (including phenothiazines, butyrophenones, thioxanthenes, metoclopramide), because. they can weaken the effect of cabergoline, aimed at reducing the concentration of prolactin.
Like other ergot derivatives, cabergoline cannot be used simultaneously with macrolide antibiotics (eg erythromycin), because. this may lead to an increase in the systemic bioavailability of cabergoline.
Dosage and administration
inside, while eating.
Prevention of lactation: 1 mg once (2 tablets of 0.5 mg), on the first day after childbirth.
Suppression of established lactation: 0.25 mg (1/2 table) 2 times a day every 12 hours for two days (total dose - 1 mg). In order to reduce the risk of orthostatic hypotension in breastfeeding mothers, a single dose of Dostinex ® should not exceed 0.25 mg.
Treatment of disorders associated with hyperprolactinemia: the recommended initial dose is 0.5 mg per week in one dose (1 tab. 0.5 mg) or in two doses (1/2 tab. 0.5 mg, for example on Monday and Thursday). Increasing the weekly dose should be carried out gradually - by 0.5 mg - with a monthly interval until the optimal therapeutic effect is achieved. The therapeutic dose is usually 1 mg per week, but can range from 0.25 to 2 mg/week. The maximum dose for patients with hyperprolactinemia should not exceed 4.5 mg per week.
Depending on tolerance, the weekly dose can be taken once or divided into 2 or more doses per week. Dividing the weekly dose into several doses is recommended when prescribing the drug at a dose of more than 1 mg / week.
In patients with hypersensitivity to dopaminergic drugs, the likelihood of developing side effects can be reduced by starting therapy with Dostinex ® at a lower dose (for example, 0.25 mg once a week), followed by a gradual increase until a therapeutic dose is reached. To improve the tolerability of the drug in the event of severe side effects, a temporary dose reduction is possible, followed by a more gradual increase (for example, an increase of 0.25 mg / week every 2 weeks).
Overdose
Symptoms: development of symptoms of hyperstimulation of dopamine receptors - nausea, vomiting, dyspeptic disorders, orthostatic arterial hypotension, confusion, psychosis, hallucinations.
Treatment: carrying out auxiliary measures aimed at removing the drug (gastric lavage), and, if necessary, maintaining blood pressure. Perhaps the appointment of dopamine antagonists.
special instructions
Before the appointment of the drug Dostinex ® for the treatment of disorders associated with hyperprolactinemia, it is necessary to conduct a complete study of the function of the pituitary gland.
In addition, an assessment of the state of the cardiovascular system, including echocardiography, should be carried out in order to identify dysfunctions of the valvular apparatus that are asymptomatic.
As with other ergot derivatives, pleural effusion/pleural fibrosis and valvulopathy have been observed in patients after long-term cabergoline use. In some cases, patients have received prior therapy with ergotoninic dopamine agonists. Therefore, Dostinex ® should not be used in patients with existing signs and / or clinical symptoms of impaired cardiac or respiratory function associated with fibrotic changes or a history of such conditions. You should stop taking the drug if there are signs of the appearance or worsening of blood regurgitation, narrowing of the lumen of the valves or thickening of the valve leaflets (see "Contraindications").
It has been found that the erythrocyte sedimentation rate increases with the development of pleural effusion or fibrosis. If an unexplained increase in ESR is detected, a chest x-ray is recommended. Plasma creatinine concentration and evaluation of renal function can also help in making a diagnosis. After discontinuation of the drug Dostinex ® in patients with pleural effusion / pleural fibrosis or valvulopathy, there was an improvement in symptoms.
It is not known whether cabergoline may worsen the condition of patients with signs of blood regurgitation. Cabergoline should not be used in the detection of fibrotic lesions of the valvular apparatus of the heart (see "Contraindications").
Fibrotic disorders may develop asymptomatically. In this regard, the condition of patients receiving long-term cabergoline therapy should be regularly monitored, and special attention should be paid to the following symptoms:
Pleuropulmonary disorders: such as shortness of breath, shortness of breath, 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 in the 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 valvular fibrosis often manifest as heart failure. In this regard, it is necessary to exclude valvular fibrosis (and constrictive pericarditis) when symptoms of heart failure appear.
The patient should be regularly monitored for the development of fibrotic disorders. The first echocardiogram should be performed 3-6 months after the start of therapy. Then this study should 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, CT) is assessed individually for each patient.
When increasing the dose, patients should be under the supervision of a physician in order to establish the lowest effective dose that provides a therapeutic effect.
After an effective dosing regimen is selected, it is recommended to conduct regular (once a month) determination of the concentration of prolactin in the blood serum. Normalization of prolactin concentration is usually observed within 2-4 weeks of treatment.
After discontinuation of the drug Dostinex ®, a relapse of hyperprolactinemia is usually observed, however, in some patients, a persistent suppression of prolactin concentration is noted for several months. In most women, ovulatory cycles persist for at least 6 months after discontinuation of the drug Dostinex ® .
Dostinex ® restores ovulation and fertility in women with hyperprolactinemic hypogonadism. Since pregnancy can occur before the return of menstruation, it is recommended to conduct pregnancy tests at least every 4 weeks during the amenorrhea period, and after the return of menstruation, every time there is a delay in menstruation by more than 3 days.
Women who wish to avoid pregnancy should use barrier methods of contraception during treatment with Dostinex ® , as well as after discontinuation of the drug until anovulation is repeated. Women who have become pregnant should be under the supervision of a doctor for the timely detection of symptoms of an enlarged pituitary gland, since during pregnancy an increase in the size of pre-existing pituitary tumors is possible.
Dostinex should be administered at lower doses to patients with severe hepatic insufficiency (Child-Pugh class C) who are indicated for long-term therapy with the drug.
With a single dose of 1 mg to such patients, an increase in AUC 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 can cause sudden sleep. In such cases, it is recommended to reduce the dose of Dostinex ® or stop therapy.
Studies on the use of the drug in elderly patients with disorders associated with hyperprolactinemia have not been conducted. The safety and efficacy of the drug in children under 16 years of age has not been established.