Bromocriptine

Pharmacological properties

dopamine receptor stimulator. inhibits the secretion of the hormone of the anterior pituitary gland - prolactin - and does not affect the normal levels of other pituitary hormones. however, bromocriptine-q is able to reduce elevated levels of stg in patients with acromegaly. this action is due to the stimulation of dopamine receptors.

In the postpartum period, prolactin is necessary to start and maintain lactation. In other periods of life, an increase in prolactin secretion leads to pathological lactation (galactorrhea) and / or a violation of ovulation and the menstrual cycle.

Bromocriptine-KB as a specific inhibitor of prolactin secretion can be used to prevent or inhibit physiological lactation, as well as for the treatment of pathological conditions caused by hypersecretion of prolactin. With amenorrhea and / or anovulatory menstrual cycles (with or without galactorrhea), bromocriptine-KB can be used to restore the menstrual cycle and ovulation.

When using Bromocriptine-KV to inhibit lactation, there is no need to limit fluid intake. In addition, Bromocriptine-KB does not affect postpartum uterine involution and does not increase the risk of thromboembolism.

Bromocriptine-KB stops the growth or reduces the size of prolactin-secreting pituitary adenomas (prolactin).

In patients with acromegaly, in addition to reducing the concentration of STH and prolactin in the blood plasma, bromocriptine-KB positively affects the clinical manifestations and glucose tolerance.

In Parkinson’s disease, which is characterized by a specific dopamine deficiency in the region of the striatum and black nuclei of the brain, stimulation of the dopamine receptors with Bromcriptin-KV can restore the neurochemical balance in the basal ganglia.

Patients with Parkinsons disease Bromocriptine-KV are usually prescribed in higher doses than those used for endocrine diseases.

Bromocriptine-KB reduces tremor, stiffness, slow movement and other symptoms of parkinsonism at all stages of the disease. The effectiveness of the drug usually lasts for several years (to date, positive treatment results have been described with a treatment duration of up to 8 years).

Bromocriptine-KB reduces the severity of symptoms of depression in patients with Parkinsons disease. This is due to its inherent antidepressant properties, which are confirmed in controlled studies in patients with endogenous or psychogenic depression who did not have Parkinsons disease.

Pharmacokinetics The effect of a decrease in prolactin content begins 1–2 hours after ingestion, reaches a maximum (decrease in prolactin concentration by more than 80%) after 5–10 hours and remains at a level close to the maximum for 8–12 hours.

Suction. After taking the drug, bromocriptine is rapidly absorbed. C_max in blood plasma is achieved within 1-3 hours

Distribution. Plasma protein binding is 96%.

Metabolism. Bromocriptine undergoes intensive metabolism during the first passage through the liver with the formation of a number of metabolites. In urine and feces, unchanged bromocriptine is practically absent. Bromocriptine has a high affinity for CYP 3A. The main metabolic pathway is hydroxylation of the proline ring in the cyclopeptide. Bromocriptine is a potent inhibitor of CYP 3A4 with a calculated IC50 of 1.69 μmol. However, due to the low therapeutic concentrations of free bromocriptine in the blood, a significant change in the metabolism of simultaneously used drugs is not expected, the clearance of which is carried out with the participation of CYP 3A4.

Removal of unchanged bromocriptine from blood plasma is biphasic, final T_½ is about 15 hours (from 8 to 20 hours).Bromocriptine and its metabolites are almost completely excreted through the liver, only 6% is excreted by the kidneys.

Special cases. In patients with impaired liver function, the rate of excretion of bromocriptine may decrease, and plasma levels may increase, which requires a correction of the dosage regimen.

The simultaneous use of inhibitors and / or potential substrates of CYP 3A4 can lead to a decrease in clearance of bromocriptine and an increase in its concentration in blood plasma.

Indications

Menstrual irregularities, female infertility

Prolactin-dependent diseases and conditions, accompanied or not accompanied by hyperprolactinemia:

• amenorrhea (which is accompanied or not accompanied by galactorrhea); oligomenorrhea;
• luteal phase deficiency;
• secondary hyperprolactinemia caused by drugs (for example, some psychotropic or antihypertensive drugs).

Prolactin-independent female infertility:

• polycystic ovary syndrome;
• anovulatory cycles (in addition to antiestrogens, such as clomiphene).

Premenstrual syndrome:

• breast tenderness, swelling associated with the phase of the cycle; flatulence; mood changes.

Hyperprolactinemia in men:

• prolactin-dependent hypogonadism (oligospermia, loss of libido, impotence).

Prolactinomas:

• conservative treatment of prolactin-secreting pituitary micro- and macroadenomas;
• preoperative preparation to reduce the volume of the tumor and facilitate its removal;
• postoperative treatment if prolactin level remains elevated.

Acromegaly:

• as an additional tool or in special cases - as an alternative to surgical or radiation treatment.

Inhibition of lactation:

• prevention or termination of postpartum lactation for medical reasons, including at the initial stage of postpartum mastitis;
• prevention of lactation after abortion.

Benign diseases of the mammary glands:

• mastalgia (including in combination with premenstrual syndrome or benign nodal or cystic changes);
• benign nodal and cystic changes, especially fibrocystic mastopathy.

Parkinsons disease:

• all stages of idiopathic Parkinsons disease and postencephalitic parkinsonism either in the form of monotherapy, or in combination with other anti-Parkinsonian drugs.

Application

Tablets should always be taken with meals. with most indications, it is necessary to gradually increase the dose to achieve the optimal response to therapy and minimize the likelihood of side effects.

The general scheme of admission. The initial dose is 1.25 mg at bedtime. After 2-3 days, the dose of Bromocriptine-KB must be increased to 2.5 mg. Further, the dose can be increased every 2–3 days by 1.25 mg until a dose of 2.5 mg is reached 2 times a day. If necessary, a further increase in the dose of the drug can be carried out according to the same scheme.

Menstrual irregularities, female infertility. At 1.25 mg (½ tablet) 2-3 times a day; if the effect is insufficient, gradually increase the dose of the drug to a dose of 2.5 mg 2-3 times a day. Continue treatment until the menstrual cycle is normalized and / or ovulation is restored. If necessary, for the prevention of relapse, treatment can be continued for several cycles.

Galactorrhea syndrome, infertility. A gradual increase in the dose of the drug according to the above scheme is proposed. Most patients with hypergalactorrhea tolerate a dose of 7.5 mg / day, which must be taken in 2-3 doses. If necessary, the dose can be increased to 30 mg / day. In infertility without an increase in the level of prolactin in the blood, the generally accepted dose is 2.5 mg 2 times a day.

Premenstrual syndrome. Treatment should be started on the 14th day of the cycle with 1.25 mg (½ tablet) per day.Gradually increasing the dose by 1.25 mg / day, bring it to a dose of 2.5 mg 2 times a day and apply until menstruation.

Hyperprolactinemia in men. At 1.25 mg (½ tablet) 2-3 times a day, gradually increasing the dose to 5-10 mg / day.

Prolactinomas A daily dose of 2.5 mg is achieved according to the general regimen. A further increase in dose (2.5 mg every 2-3 days) should be carried out according to the following scheme: 2.5 mg every 8 hours; 2.5 mg every 6 hours; 5 mg every 6 hours. A therapeutic effect is expected until a dose of 30 mg / day is reached.

The appointment of bromocriptine to children and adolescents (aged 7-17 years) is carried out by a pediatric endocrinologist. For children aged 7 years and older, prescribe 1 mg 2 or 3 times a day, gradually increasing the dose as necessary to maintain an adequately reduced plasma prolactin level.

The maximum recommended dose for children and adolescents aged 7-12 years is 5 mg / day, 13-17 years - 20 mg / day.

Acromegaly. A daily dose of 2.5 mg is achieved according to the general regimen. A further increase in dose (2.5 mg every 2-3 days) should be carried out according to the following scheme: 2.5 mg bromocriptine every 8 hours; 2.5 mg every 6 hours; 5 mg every 6 hours

The maximum recommended dose for children and adolescents aged 7-12 years is 10 mg / day; 13-17 years - 20 mg.

Inhibition of lactation. On the first day, take 2.5 mg in 2 divided doses, and in the next 2-3 days, the dose should be increased up to 2 times a day, 2.5 mg of bromocriptine. Continue treatment for 14 days. There is no need for a gradual increase in the dose of the drug.

To prevent the onset of lactation, the drug should be started several hours after the birth or abortion, however, only after stabilization of vital functions 2 or 3 days after the drug is discontinued, insignificant milk secretion sometimes occurs. It can be stopped by resuming taking the drug in the same dose for another 1 week.

Lactation Prevention On the day of birth, take 2.5 mg, and in the future - 2 times 2.5 mg of Bromocriptine-KV for 14 days. There is no need for a gradual increase in the dose of the drug.

Benign diseases of the mammary glands. According to the above scheme, it is necessary to achieve a dose of the drug 2 times 2.5 mg.

Parkinsons disease. It is necessary to follow the scheme of a gradual increase in dose.

1st week: 1.25 mg / day before bedtime.

2nd week: 2.5 mg / day before bedtime.

3rd week: 2 times 2.5 mg / day.

4th week: 3 times 2.5 mg / day.

After that, depending on the patient’s condition, the next 3-14 days, the dose of the drug can be increased by 2.5 mg. The dose increase can be continued until the optimum is reached, which is in the range of 10–40 mg Bromocriptine-KB per day.

If adverse reactions occur during dose selection, the daily dose should be reduced and maintained at a lower level for at least 1 week. When stopping side effects, the dose can be increased again.

Patients with motor impairment who take levodopa are advised to reduce the dose of levodopa before using Bromocriptine-KV. After achieving a satisfactory clinical effect in the treatment of Bromocriptine-KB, a further gradual reduction in the dosage of levodopa can be carried out. In some patients taking Bromocriptine-KB, a complete abolition of levodopa is possible.

With an increase in the dose of bromocriptine, it becomes possible to reduce the dose of levodopa and establish equilibrium with the use of drugs in optimal doses.

Elderly patients do not require dose adjustment. With impaired liver function, a delay in the release of the drug from the body and an increase in the concentration of bromocriptine in the blood plasma may occur. In this regard, it may be necessary to change the dose of the drug.

Contraindications

Hypersensitivity (allergy) to bromocriptine or other ergot alkaloids;

• uncontrolled hypertension;
• preeclampsia (including eclampsia, preeclampsia);
• AH during pregnancy and the postpartum period;
• IHD and other severe cardiovascular diseases;
• severe mental disorders currently and / or in history;
• childrens age up to 7 years (experience with the drug is limited);
• regarding long-term treatment: pathology of the valvular apparatus of the heart, confirmed by echocardiography.

Side effects

From the side of the central nervous system and the peripheral nervous system: headache, dizziness, motor disturbances, confusion, psychomotor agitation, hallucinations, paresthesias, psychotic disorders, insomnia, increased libido, hypersexuality, increased drowsiness in the daytime, sudden falling asleep.

From the senses: impaired vision, "blurred vision", tinnitus.

From the cardiovascular system: arterial hypotension, orthostatic hypotension (very rarely leads to loss of consciousness), pericardial effusion, constrictive pericarditis, tachycardia, bradycardia, arrhythmia; fibrosis of heart valves, reversible pallor of fingers and toes caused by hypothermia (especially in patients with a history of Raynauds syndrome).

From the respiratory system: nasal congestion, pleural effusion, pleural fibrosis, pleurisy, pulmonary fibrosis, shortness of breath.

From the digestive system: nausea, constipation, vomiting, dry mouth; diarrhea, abdominal pain, retroperitoneal fibrosis, gastrointestinal ulcer, gastrointestinal bleeding (stool black, blood in the vomit), dyskinesia.

Dermatological reactions: hair loss.

Allergic reactions: skin manifestations.

From the musculoskeletal system: spasms of the calf muscles.

Others: fatigue; peripheral edema, in the case of a sharp discontinuation of the drug - the development of a condition similar to malignant antipsychotic syndrome.

When using the drug in high doses (like other dopamine agonists), a reversible violation of sexual behavior, increased libido and hypersexuality were rarely observed, which disappeared after a decrease in the dose of the drug or discontinuation of treatment. In individuals with individual intolerance to any component of the drug, hypersensitivity reactions are possible.

The use of bromocriptine-KV to suppress physiological lactation in the postpartum period was rarely accompanied by the development of hypertension, myocardial infarction, seizures, stroke, or mental disorders.

special instructions

Hyperprolactinemia can be idiopathic, drug-induced, or caused by a disease of the hypothalamus or pituitary gland. a set of studies should be carried out to identify pituitary tumors and decide on the feasibility of treating such patients in order to reduce hyperprolactinemia. bromocriptine-q effectively reduces prolactin levels in such patients, but such therapy does not eliminate the need for radiation therapy or surgery if necessary.

If treatment with the drug is prescribed to women with a pathology that is not associated with hyperprolactinemia, the drug should be used in the minimum effective dose necessary to relieve symptoms; this is necessary in order to avoid a decrease in the concentration of prolactin in the blood plasma below the normal level and the development of dysfunction of the corpus luteum. In patients who will be prescribed treatment with the drug for mastalgia, nodal and / or cystic changes in the mammary glands, malignant neoplasms should be excluded using appropriate diagnostic methods.

Attention should be paid to the signs and symptoms of pleuropulmonary diseases such as shortness of breath, shortness of breath, coughing, or chest pain; possible manifestation of heart failure as pericardial fibrosis. In the event of such symptoms, a constrictive pericardium should be excluded.

Use in the postpartum period. Rarely reported development in women taking bromocriptine in the postpartum period to inhibit lactation, serious adverse reactions, including hypertension, myocardial infarction, seizures, stroke, or mental disorders.In some patients, the development of seizures or cerebrovascular accident was preceded by severe headache and / or transient visual impairment. Although a causal relationship between these phenomena and the use of bromocriptine has not been established, in women taking the drug in the postpartum period to inhibit lactation, as in patients receiving Bromocriptine-KV for any other indication, blood pressure should be periodically monitored. If hypertension develops or a pronounced progressive headache that cannot be eliminated (accompanied or not accompanied by visual impairment), or signs of disorders of the central nervous system, the drug should be discontinued and the patient should be examined immediately.

Particular care should be taken in patients who have recently taken or continue to take drugs that affect blood pressure, such as vasoconstrictor drugs (sympathomimetics or ergot alkaloids, including ergometrine or methylergometrine). Although there is no conclusive evidence of an interaction between Bromocriptine-KB and these drugs, their simultaneous use in the postpartum period is not recommended.

Use for prolactin-secreting adenomas. Since patients with pituitary macroadenomas may exhibit signs of hypopituitarism due to compression or destruction of the pituitary tissue, for these patients, a full assessment of the pituitary gland functions and appropriate replacement therapy should be performed before the administration of Bromcriptin-KB. In patients with secondary adrenal insufficiency, corticosteroid replacement therapy is important.

In patients with pituitary macroadenomas, the dynamics of tumor size should be systematically evaluated. If there is an increase in the tumor, surgical treatment should be considered.

Careful monitoring of pregnant women with pituitary adenoma should be ensured, since prolactin-secreting adenomas during pregnancy can increase in size. In such patients, treatment with bromocriptine often leads to a decrease in tumor size and rapid positive dynamics from visual field defects. In severe cases, the development of compression of the optic or other cranial nerves can serve as the basis for emergency surgery on the pituitary gland.

In clinical trials, the number of patients over the age of 65 was insufficient to conduct a comparative assessment of the effectiveness of treatment with Bromocriptine-KV with young patients. However, in clinical trials and medical practice, the tolerability of the drug in patients aged 65 years compared with younger patients was the same. It is necessary to take into account the hardly predicted tolerance of the drug in this category of patients.

During treatment with Bromocriptineom-KV, careful monitoring of patients with a history of gastric and duodenal ulcer is necessary.

A thorough examination and monitoring of patients with pleuropulmonary diseases of unknown etiology and the termination of drug therapy with the progression of disorders are necessary.

For early diagnosis of retroperitoneal fibrosis at a reversible initial stage of the process, the doctor is advised to monitor the manifestations of symptoms such as back pain, swelling of the lower extremities, impaired renal function. Bromocriptine-KV should be abolished with confirmed fibrotic changes in the retroperitoneal space or with suspected presence.

A known complication of macroprolactin is loss of visual fields. Effective drug treatment reduces hyperprolactinemia and eliminates visual field disorders. Nevertheless, in some patients, secondary changes in the visual fields are possible, despite the normalization of prolactin levels and a decrease in tumor size.This may be due to the displacement of visual crosshairs due to the release of volume in the Turkish saddle. In this case, a reduction in the dose of bromocriptine, which leads to an increase in prolactin levels and an increase in the size of the tumor to some extent, can help to eliminate visual field defects. In this regard, monitoring of visual fields in patients with macroprolactinoma is indicated for the early detection of secondary attacks of visual fields caused by spatial protrusion of visual intersection in the saddle cavity and adaptation to the action of a given dose of the drug. Cases of cerebrospinal rhinorrhea have been reported in some patients with prolactin-secreting adenoma who are taking Bromocriptine-KB. According to the results of clinical studies, cerebrospinal rhinorrhea can be caused by a decrease in the volume of invasive tumors.

Patients with rare hereditary forms of galactose intolerance, severe lactose deficiency, glucose-galactose malabsorption should not take Bromocriptine-KV.

The effectiveness and safety of the drug have been established in children aged 7 years and adolescents with prolactinomas and acromegaly. In clinical studies and medical practice, the tolerance of the drug in adults and children was the same. It is necessary to take into account the hardly predicted sensitivity to the drug in this category of patients.

Violations of control of motivation. Patients should be monitored regularly if there is a suspected risk of developing motivation control. Patients and those who monitor them should be aware that when using dopamine agonists, in particular bromocriptine, there may be a violation of the control of motivation, namely, manifestations such as gambling, increased libido, hypersexuality, craving for embezzlement or shopping, bulimia, overeating. With such symptoms, the dosage of the drug should be reduced or therapy should be gradually discontinued.

Use during pregnancy and lactation. In patients who wish to become pregnant, after the pregnancy is confirmed, drug withdrawal is possible, except in cases where the possible positive effect of treatment exceeds the potential risk to the fetus.

The abolition of Bromocriptine-KV during pregnancy did not lead to an increase in the frequency of cases of spontaneous abortion.

Clinical experience shows that the use of the drug during pregnancy does not adversely affect its course or childbirth.

If pregnancy occurs when the patient has pituitary adenomas and treatment with Bromocriptine-KV is stopped, careful monitoring of the patient throughout the entire period of pregnancy is necessary. In the case of signs of a pronounced increase in prolactinoma, for example, a headache or narrowing of the visual fields, treatment with Bromcriptin-KV can be resumed or surgery may be prescribed.

Since Bromocriptine-KV inhibits lactation, it should not be prescribed to women who do not plan to interrupt breastfeeding.

Drug treatment can restore fertility. No embryotoxic or teratogenic effects of bromocriptine have been identified. Women of reproductive age who do not want to become pregnant should use a reliable method of contraception.

Children. Due to the lack of experience in the use of the drug should not be used in children under the age of 7 years.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Patients whose activities are related to driving vehicles or working with mechanisms should be especially careful, because sometimes, especially in the early days of treatment, arterial hypotension may develop, which leads to a decrease in the rate of psychomotor reactions.

During treatment, drowsiness and episodes of sudden falling asleep were noted, especially in patients with Parkinsons disease. Episodes of sudden falling asleep against the background of daytime wakefulness, which occurred without preliminary drowsiness, were extremely rare. Before prescribing the drug, the doctor should inform the patient about these risk factors and recommend that you refrain from driving vehicles, working with mechanisms, and also from engaging in other potentially dangerous activities that require increased attention and speed of reactions. With the development of severe drowsiness or the appearance of episodes of sudden falling asleep, you should reduce the dose of the drug or completely cancel it.

Interactions

Bromocriptine is both a substrate and an inhibitor of the cyp 3a4 enzyme. caution should be exercised when prescribing bromocriptine and other cyp 3a4 inhibitors and / or substrates (azole antifungal agents, HIV protease inhibitors). simultaneous administration of erythromycin, josamycin, other macrolide antibiotics and bromocriptine-q causes an increase in the concentration of bromocriptine in blood plasma. the simultaneous use of octreotide and bromocriptine in patients with acromegaly is accompanied by an increase in the level of the latter in blood plasma.

The therapeutic efficacy of bromocriptine, associated with the stimulation of central dopamine receptors, may be reduced with the use of dopamine receptor antagonists such as antipsychotics (phenothiazines, butyrophenones and thioxanthenes), as well as metoclopramide and domperidone.

The simultaneous administration of the drug Bromocriptine-KV with antihypertensive drugs can lead to increased severity of a decrease in blood pressure.

Bromocriptine-KV can be prescribed either in the form of monotherapy, or in combination with other antiparkinsonian drugs (both in the early and late stages of the disease). The combination with levodopa leads to increased antiparkinsonian action, often makes it possible to reduce the dose of levodopa. The use of Bromocriptine-KV preparation in patients receiving treatment with levodopa is especially advisable when the therapeutic effect of levodopa is weakened or when complications such as pathological involuntary movements (choreoathetoid dyskinesia and / or painful dystonia), depletion effect syndrome until the dose of levodopa is completed, the phenomenon of “ on-off. "

There may be a deterioration in the tolerance of the drug Bromocriptine-KV with the use of ethanol.

Overdose

Symptoms in all cases of an overdose of bromocriptine taken in isolation, no fatal outcomes were noted. the maximum single dose currently known is 325 mg. with an overdose, symptoms such as nausea, vomiting, dizziness, arterial hypotension, orthostatic hypotension, tachycardia, drowsiness, lethargy, hallucinations were observed.

In case of accidental administration of the drug Bromocriptine-KV inside by children (separate reports), the development of vomiting, fever and drowsiness was noted. Improvement in the condition of patients occurred suddenly or a few hours after the appropriate therapy.

Treatment. In case of an overdose, it is recommended to take activated charcoal; gastric lavage is possible immediately after taking the drug. The treatment of acute poisoning is symptomatic. To stop vomiting or hallucinations, metoclopramide can be used.

Storage conditions

In the original packaging at a temperature not exceeding 25 ° C.