Pharmacological properties
Pharmacodynamics. Bromocriptine - the active ingredient of the drug Bromocriptine-Richter, tablets 2.5 mg - is an inhibitor of prolactin secretion and a stimulator of dopamine receptors. The scope of application of Bromocriptine includes endocrinological and neurological indications. The pharmacological properties of the drug are discussed below for each type of indication.
Endocrinological indications for use
Bromocriptine inhibits prolactin secretion without affecting the normal levels of other hormones released by the anterior pituitary gland.
In patients with acromegaly, bromocriptine reduces elevated levels of growth hormone in the blood plasma, and therefore alleviates the clinical manifestations of the disease and improves glucose tolerance.
Bromocriptine prevents or suppresses lactation and restores prolactin-dependent menstrual cycles and ovulation. It is an effective treatment for amenorrhea and anovulation (with or without galactorrhea).
Bromocriptine does not increase the risk of thromboembolism; it has been shown to reduce the size of pituitary adenomas that secrete prolactin (prolactinomas).
Bromocriptine reduces the severity of clinical symptoms of polycystic ovary syndrome.
neurological evidence
Due to its dopaminergic activity, bromocriptine is effective in the treatment of patients with Parkinson's disease - provided that it is administered in doses exceeding those recommended for endocrinological indications. This disorder is characterized by a nigrostriatal dopamine deficiency. Stimulation of dopamine receptors by bromocriptine is able to restore neurochemical balance.
Clinically, bromocriptine alleviates the symptoms of Parkinson's disease (e.g., tremor, muscle rigidity, bradykinesia) and depression at all stages of the disease. Bromocriptine can be used alone or in combination with other drugs for Parkinson's disease.
Combination therapy reduces the required dose of levodopa and therefore delays the recurrence of motor abnormalities. Thus, bromocriptine treatment can provide a reduction in the dose of other drugs used in combination with it, in particular levodopa. This may relieve patients from certain undesirable effects of levodopa, such as end-of-dose worsening, on-off phenomena and dyskinesia.
Pharmacokinetics. Bromocriptine is rapidly and extensively absorbed from the gastrointestinal tract after oral administration. The parent compound and its metabolites are metabolized in the liver and excreted in the feces; only 6% of the compound is excreted in the urine.
The binding of the drug to blood plasma proteins is 96%.
C max of the drug in blood plasma is achieved within 1-3 hours. The effect of reducing prolactin levels is manifested already 1-2 hours after oral administration, reaches a maximum in approximately 5 hours and is maintained for 8-12 hours. The process of removing the original substance from blood plasma has a two-phase nature, and T ½ is approximately 15 hours.
Elderly patients do not have a direct effect on the pharmacokinetics of bromocriptine. However, in patients with impaired liver function, delayed elimination may lead to increased plasma levels of the drug, which may require dose adjustment.
There is no evidence of a direct effect of elderly patients on the pharmacokinetics and tolerability of bromocriptine. However, in patients with impaired liver function, the rate of elimination may be reduced and the plasma levels of the drug may be correspondingly increased, requiring dose adjustment.
Biotransformation. Bromocriptine undergoes extensive presystemic biotransformation in the liver, which is reflected in a complex metabolite profile and the almost complete absence of the parent substance in urine and feces. It exhibits high affinity for CYP 3A, and the main metabolic pathway is hydroxylation of the proline ring of the cyclopeptide component. Therefore, it is expected that inhibitors and/or potent substrates of CYP 3A4 will suppress the elimination of bromocriptine and lead to an increase in its level. Bromocriptine is also a potent inhibitor of CYP 3A4. However, given the low therapeutic concentrations of free bromocriptine in patients, no significant changes in the metabolism of a second drug, the elimination of which is mediated by the CYP 3A4 system, should be expected.
Indication
Menstrual irregularities and female sterility
Diseases dependent on prolactin levels and conditions with or without hyperprolactinemia. Amenorrhea (with or without galactorrhea); oligomenorrhea. Luteal phase insufficiency. Secondary hyperprolactinemia caused by other drugs (e.g. some psychotropic or antihypertensive drugs).
Prolactin-independent female infertility. Polycystic ovary syndrome. Anovulatory cycles (induced by antiestrogens, such as clomiphene). Infertility associated with hyperprolactinemia. Bromocriptine has been used successfully to treat a number of women with infertility without overt hyperprolactinemia.
Premenstrual syndrome. Breast pain; breast swelling associated with the phase of the cycle; flatulence; mood swings.
Hyperprolactinemia in men (with or without galactorrhea). Prolactin-dependent hypogenitalism (oligospermia, loss of libido, impotence).
Bromocriptine can be used as a first-line drug for the treatment of macroadenomas and as an alternative to surgical treatment (transsphenoidal removal of the pituitary gland) in patients with microadenomas.
Preoperative preparation to reduce the size of the tumor to limit the incision.
Postoperative treatment if prolactin levels remain elevated.
Acromegaly. Used as an adjunct to radiation therapy or surgery to reduce growth hormone levels in the systemic circulation of patients with acromegaly.
It is used as a special remedy that is an alternative to radiation therapy or surgery.
Suppression of lactation. Prevention or suppression of lactation after childbirth for medical reasons, including the early stages of postpartum mastitis. This drug is not recommended for routine suppression of lactation, for the relief of postpartum pain symptoms, or for engorgement of the mammary glands. Prevention of lactation after abortion.
Benign neoplasm of the breast. Mastalgia (including those associated with premenstrual syndrome or benign focal or cystic changes). Benign focal and/or cystic conditions, including fibrocystic breast disease.
Parkinson's disease. All stages of idiopathic Parkinson's disease: Bromocriptine is used either alone or in combination with levodopa to control the condition of previously untreated individuals and those with severe on-off phenomena. It may help patients who are unresponsive to or intolerant of levodopa, and those whose response to levodopa is diminished. Postencephalitic Parkinson's disease: It may be used alone or in combination with other drugs for the treatment of Parkinson's disease.
Treatment of patients with cyclic benign breast disease and premenstrual syndrome (see Features of use).
Application
Dosage. The drug should always be taken with food. For most indications, the optimal response with a minimum of side effects is achieved by gradually increasing the dose.
Adults: The maximum dose should be limited to 30 mg/day.
Recommended dosage regimen. At the beginning of treatment, a dose of 1.25 mg is used before bedtime, with a gradual increase after 2-3 days to 2.5 mg before bedtime. Then the dose can be increased by 1.25 mg at intervals of 2-3 days until a daily dose of 2.5 mg is reached twice a day. Further dose increases, if necessary, are carried out in a similar way.
Prevention of lactation. 2.5 mg on the day of delivery followed by 2.5 mg twice daily for 14 days. Gradual dose escalation of bromocriptine is not required for these indications.
Suppression of lactation. 2.5 mg on day 1, followed by an increase in dose to 2.5 mg 2 times a day after 2-3 days. The course of treatment lasts 14 days; for these indications, a gradual increase in the dose of bromocriptine is not required.
Hypogenitalism / galactorrhea syndrome / sterility. Bromocriptine is administered gradually according to the scheme. In most patients with hyperprolactinemia, an adequate response is achieved by using a dose of 7.5 mg / day (in several doses), but doses up to 30 mg / day have been used. In patients with infertility without an increase in plasma prolactin levels, the usual dose is 2.5 mg 2 times a day.
Prolactinomas. Bromocriptine is administered gradually according to the scheme. After reaching a daily dose of 2.5 mg, the dose can be increased by 2.5 mg/day at intervals of 2-3 days as follows: 2.5 mg - every 8 hours, 2.5 mg - every 6 hours, 5 mg - every 6 hours. Reactions in patients were observed when using doses up to 30 mg/day.
Acromegaly. Bromocriptine is administered gradually according to the scheme. After reaching a daily dose of 2.5 mg, the dose can be increased by 2.5 mg/day at intervals of 2-3 days as follows: 2.5 mg - every 8 hours, 2.5 mg - every 6 hours, 5 mg - every 6 hours.
Parkinson's disease. Bromocriptine is administered gradually as follows:
1st week: 1.25 mg at bedtime.
Week 2: 2.5 mg at bedtime.
Week 3: 2.5 mg twice a day.
4th week: 2.5 mg 3 times a day.
The daily dose may then be increased by 2.5 mg over a period of 3-14 days depending on the patient's response. The dose may be increased until the optimal dose is reached; this is usually 10-30 mg/day. At the same time, the levodopa dose may be gradually reduced until an optimal balance is achieved.
Use in the elderly: There is no evidence that bromocriptine poses a particular risk to the elderly.
Patients with impaired liver function. In patients with impaired liver function, the rate of drug elimination may decrease and, accordingly, the level of the drug in the blood plasma may increase, which requires dose adjustment.
Contraindication
Hypersensitivity to the active substance, other ergot alkaloids, or any of the excipients.
In case of long-term treatment: signs of heart valve insufficiency obtained during echocardiography performed before the start of treatment.
Bromocriptine is contraindicated for use to suppress lactation in patients with a history of atherosclerotic heart disease or other severe cardiovascular disease or symptoms/history of severe psychiatric disorders. Patients with these conditions who require bromocriptine for macroadenoma should receive it only if the expected benefits outweigh the potential risks (see Precautions).
Bromocriptine should not be taken simultaneously with other ergot alkaloids.
Bromocriptine should not be prescribed to patients with a history of fibrotic disorders or signs of valvular heart disease on echocardiography performed before treatment.
Treatment during pregnancy is described in the section "Use during pregnancy and breastfeeding".
Side effects
Nausea, vomiting, anorexia, headache, dizziness, and fatigue may occur during the first few days of treatment; however, these reactions usually do not require discontinuation of bromocriptine.
The risk of side effects can be reduced by gradually increasing the dose and taking bromocriptine tablets with food. If necessary, the daily dose can be reduced and maintained at this level for several days. After the side effects disappear, a gradual increase in the dose can be attempted.
Bromocriptine may cause orthostatic hypotension, therefore, blood pressure in ambulatory patients should be measured in the upright position.
In patients with Parkinson's disease who use high doses of the drug, drowsiness, hallucinations, confusion, visual disturbances, dry mouth, calf muscle cramps and retroperitoneal fibrosis may occur (see Precautions). All of these undesirable effects are dose-dependent.
During long-term treatment, especially in patients with a history of Raynaud's phenomenon, reversible cold-induced pallor of the fingers and toes has been observed.
In extremely rare cases (in postpartum women receiving bromocriptine to suppress lactation), serious side effects have been reported, including hypertension, myocardial infarction, or stroke, although a causal relationship between these events and the use of the drug is unknown. Some patients have experienced severe headaches and/or temporary visual disturbances prior to the stroke.
Very rarely, valvular heart disease (including regurgitation) and related disorders (pericarditis and pericardial effusion) have developed.
Patients with cirrhosis may develop hyponatremia and hepatic encephalopathy.
Very rarely, bromocriptine can cause sudden daytime sleepiness.
Patients taking dopamine agonists, including Bromocriptine-Richter, may experience pathological gambling, increased libido, hypersexuality, a tendency to impulsive spending or shopaholic behavior, and impulsive gluttony (see Precautions).
Dopamine agonists, which belong to the group of ergot alkaloids, can increase the risk of heart valve regurgitation.
Adverse reactions, grouped by system organ class, are listed below.
Metabolism and nutrition disorders: often - anorexia.
Mental disorders: infrequently - confusion, hallucinations, psychomotor agitation; rarely - insomnia, mental disorders; very rarely - hypersexuality, increased libido, pathological gambling.
From the nervous system: often - headache, drowsiness; infrequently - dizziness, dyskinesia; rarely - drowsiness, paresthesia; very rarely - sudden sleepiness, cerebrospinal fluid rhinorrhea.
On the part of the organ of vision: very rarely - visual impairment, blurred vision.
From the organs of hearing and balance: rarely - tinnitus.
From the heart: rarely - pericardial effusion, constrictive pericarditis, tachycardia, bradycardia, arrhythmia; very rarely - myocardial infarction, heart valve insufficiency.
Vascular disorders: infrequently - orthostatic hypotension; very rarely - arterial hypertension, pallor.
From the respiratory system, chest organs and mediastinum: often - nasal congestion; rarely - pleural effusion, pleural fibrosis, pulmonary fibrosis, pleurisy, difficulty breathing.
From the digestive system: often - nausea, constipation; infrequently - dry mouth, vomiting; rarely - abdominal pain, retroperitoneal fibrosis, gastrointestinal bleeding, gastrointestinal ulcers.
Skin and subcutaneous tissue disorders: infrequently - allergic skin reactions, hair loss.
Musculoskeletal and connective tissue disorders: infrequently - calf muscle cramps.
General disorders and administration site conditions: uncommon - fatigue; rare - peripheral edema; very rare - neuroleptic malignant syndrome (bromocriptine withdrawal syndrome).
Special instructions
Bromocriptine is not recommended for use after or during childbirth in women with hypertension, atherosclerotic heart disease and/or a history of severe cardiovascular disease or serious psychiatric disorders. In postpartum women using bromocriptine, blood pressure should be carefully monitored at regular intervals, especially during the first days of treatment.
Particular caution is required in patients who are using (or have recently used) concomitant treatment with drugs that can affect blood pressure.
The concomitant use of bromocriptine with vasoconstrictors such as sympathomimetics or ergot alkaloids, including ergometrine or methylergometrine, during labor is not recommended.
In rare cases, postpartum women who used bromocriptine to suppress lactation have experienced serious side effects, including myocardial infarction, hypertension, stroke, or psychiatric disorders. Some patients have experienced severe headaches and/or temporary visual disturbances prior to the stroke.
In case of hypertension, severe and persistent headache with visual disturbances or any signs of CNS toxicity, treatment should be discontinued immediately.
Patients may develop hyperprolactinemia of idiopathic or drug-induced origin, or due to diseases of the hypothalamus or pituitary gland. Bromocriptine effectively lowers prolactin levels in patients with pituitary tumors; however, it does not eliminate the need for radiation therapy or surgery in the case of acromegaly.
Women of reproductive age with conditions not associated with hyperprolactinemia should be treated with the lowest effective dose. This precaution is necessary to avoid suppression of prolactin secretion to subnormal levels with subsequent disruption of the corpus luteum. During treatment, such patients should use a reliable non-hormonal method of contraception, since oral contraceptives are known to increase plasma prolactin levels.
Women who need to use bromocriptine for a long period of time should have a gynecological examination (including cytological examination). Women in menopause are recommended to undergo an examination every 6 months, and women of reproductive age - once a year.
Several cases of gastrointestinal bleeding and bleeding from gastric ulcers have been reported. If this occurs, bromocriptine should be discontinued immediately. Patients with a history of gastric ulcer should be closely monitored during treatment with bromocriptine.
For patients with acromegaly and a history of gastric ulcer, other treatments should be preferred whenever possible. If bromocriptine cannot be substituted by another agent, the patient should be advised to report any gastrointestinal side effects immediately to the physician.
Patients with severe cardiovascular or psychiatric disorders who use bromocriptine for macroadenoma should take it only if the expected benefits outweigh the potential risks.
Since in patients with pituitary macroadenomas the disease may be accompanied by pituitary hypofunction as a result of compression or destruction of pituitary tissue, before starting bromocriptine, patients should undergo a complete examination of pituitary function and initiate appropriate replacement therapy if necessary. In patients with secondary adrenal insufficiency, replacement therapy with corticosteroids is important.
Changes in tumor size should be carefully monitored in patients with pituitary macroadenomas, and in the event of tumor growth, the feasibility of surgical procedures should be considered.
If patients with adenoma become pregnant after taking bromocriptine, careful monitoring of their health is mandatory. Prolactin-secreting adenomas can grow during pregnancy. In such patients, treatment with bromocriptine often leads to a decrease in tumor size and a rapid decrease in visual field defects. In severe cases, compression of the optic and other cranial nerves may require urgent adrenal surgery.
Visual field defects are a known complication of macroprolactinomas. Effective treatment with bromocriptine leads to a reduction in tumor size and hyperprolactinemia, and often to resolution of visual impairment. However, some patients may later develop secondary visual field defects despite normalized prolactin levels and tumor size reduction. In such cases, visual field defects may improve after bromocriptine dosage reduction, although prolactin levels may remain slightly elevated and tumor growth may be modest. Therefore, visual field monitoring is recommended for early detection of secondary visual field defects and appropriate dose adjustment.
Some patients with prolactin-secreting adenomas treated with bromocriptine have experienced cerebrospinal fluid rhinorrhea. Available evidence suggests that this may be due to a reduction in the size of the proliferating tumors.
During the first few days of treatment, patients may sometimes experience hypotension.
Treatment of Parkinson's disease with high doses requires caution in patients with a history of psychosis or severe cardiovascular disorders.
Pleural and pericardial effusions, pleural and pulmonary fibrosis, and constrictive pericarditis have occasionally been reported in patients receiving bromocriptine, especially over long periods and at high doses. Patients with pleural-pulmonary disorders require careful evaluation to determine the cause; in such cases, discontinuation of bromocriptine therapy should be considered.
Retroperitoneal fibrosis has been reported in a few patients treated with bromocriptine, particularly for long periods and at high doses. To ensure that retroperitoneal fibrosis is detected in its early, reversible stages, it is recommended to monitor its manifestations (e.g. back pain, lower extremity swelling, renal dysfunction) in this category of patients.
If fibrotic changes in the retroperitoneal space are diagnosed or suspected, treatment with bromocriptine drugs should be discontinued.
Patients should be closely monitored during treatment for signs of progressive fibrotic disorders. If retroperitoneal fibrosis is diagnosed or suspected, bromocriptine treatment should be discontinued.
Bromocriptine treatment may be associated with somnolence and sudden sleep onset, particularly in patients with Parkinson's disease. Sudden onset of sleep during daily activities, in some cases without the patient being aware of it and without warning signs, has been observed very rarely. Patients should be informed of this possibility and advised to exercise caution when driving or operating machinery during treatment with bromocriptine. Patients who experience somnolence and/or sudden sleep onset should refrain from driving or operating machinery. Furthermore, a dose reduction or discontinuation of treatment should be considered.
Impulse control disorders. Patients should be monitored regularly for the development of impulse control disorders. Patients and caregivers should be informed of the possibility of developing behavioral symptoms of impulse control disorders in patients taking dopamine agonists, including Bromocriptine-Richter, including pathological gambling, increased libido, hypersexuality, compulsive spending or shopaholic behavior, and compulsive overeating. If such symptoms occur, consideration should be given to reducing the dose of the drug/gradually discontinuing its use.
This medicine contains 41 mg of lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Use during pregnancy and lactation. Pregnancy. In patients planning pregnancy, bromocriptine, like all other drugs, should be discontinued when pregnancy is confirmed, unless there are medical contraindications to continued therapy. No increase in the number of abortions has been observed after discontinuation of bromocriptine during this period. Clinical experience has shown that the use of bromocriptine during pregnancy does not adversely affect its course or outcome.
If pregnancy occurs in a patient with a pituitary adenoma and bromocriptine treatment has been stopped, close medical supervision throughout the pregnancy is essential. In patients who develop signs of marked enlargement of the prolactinoma, such as headache or visual field deterioration, bromocriptine treatment may be resumed or surgery may be considered.
Breastfeeding: Since bromocriptine inhibits lactation, it should not be used in nursing mothers.
Children. Bromocriptine-Richter tablets are not recommended for use in children under 7 years of age due to insufficient data on safety and efficacy.
Bromocriptine has been used to treat prolactinoma and gigantism (acromegaly) in patients ≥7 years of age, and such cases have been described in the literature. There are isolated data on the use of bromocriptine in pediatric practice in patients under 7 years of age. Safety data are limited, especially with long-term use.
Ability to influence the reaction rate when driving vehicles or operating other mechanisms. In the first few days of treatment, patients may experience arterial hypotension, visual disturbances and dizziness, therefore, they should be especially careful when driving vehicles or operating mechanisms.
Patients who experience drowsiness and/or sudden sleep onset should be advised to refrain from driving or engaging in activities where impaired alertness may endanger other people.
Interactions
The tolerability of bromocriptine may decrease under the influence of alcohol.
Concomitant use of erythromycin, other macrolide antibiotics and octreotide may increase the plasma levels of bromocriptine.
Dopamine antagonists (e.g. butyrophenones, phenothiazines) may reduce the prolactin-lowering and Parkinson's effects of bromocriptine.
Metoclopramide and domperidone may weaken the prolactin-lowering effect of bromocriptine.
Sympathomimetic drugs, such as phenylpropanolamine, isometheptene, increase the risk of toxicity.
Concomitant use with other ergot alkaloids should be avoided.
Bromocriptine should be used with caution in combination with CYP 3A4 inhibitors (e.g. azole fungicides, HIV protease inhibitors) (see Pharmacological properties).
Overdose
Signs and symptoms: Overdose of bromocriptine is likely to produce symptoms of excessive stimulation of dopaminergic receptors and may include vomiting, nausea, dizziness, hypotension, orthostatic hypotension, tachycardia, drowsiness, somnolence, lethargy, hallucinations and confusion.
There have been isolated reports of accidental ingestion of bromocriptine by children. They have experienced side effects such as vomiting, drowsiness, and fever. The patients' condition has returned to normal spontaneously within a few hours or after appropriate treatment.
Treatment: General supportive measures should be used to remove any unabsorbed drug and to maintain blood pressure as needed.
Storage conditions
At a temperature not exceeding 30 °C in a place protected from light.
