Bromocriptin-Richter (Tablets) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

Contact Information

GEDEON RICHTER Plc. (Hungary)

ATC Codes

G02CB01 (Bromocriptine)

N04BC01 (Bromocriptine)

Active Substance

Bromocriptine (Rec.INN registered by WHO)

Dosage Form

Bromocriptine-Richter

Tablets 2.5 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Tablets are almost white, round, flat, with a bevel, with a score on one side and an engraving “2.5” on the other. The tablet can be divided into equal doses.

Excipients: colloidal silicon dioxide, magnesium stearate, talc, povidone-K30, corn starch, microcrystalline cellulose (type 102), lactose monohydrate.

30 pcs. – dark glass bottles (1) – cardboard packages.

Clinical-Pharmacological Group

Prolactin secretion inhibitor. Antiparkinsonian drug

Pharmacotherapeutic Groups

• Other drugs for the treatment of gynecological diseases; prolactin secretion inhibitors
• Antiparkinsonian drugs; dopamine receptor agonists

Pharmacological Action

Bromocriptine is an inhibitor of prolactin secretion and a stimulator of dopamine receptors. The scope of application of bromocriptine is divided into endocrinological and neurological indications.

Mechanism of action

Endocrinological properties

Bromocriptine inhibits the secretion of the anterior pituitary hormone prolactin, without affecting the normal secretion of other pituitary hormones. However, Bromocriptine can reduce elevated concentrations of growth hormone (GH) in patients with acromegaly. This action is due to the stimulation of dopamine receptors.

In the postpartum period, prolactin is necessary for the initiation and maintenance of postpartum lactation. At other times of life, increased prolactin secretion leads to pathological lactation (galactorrhea) and/or disturbances in ovulation and the menstrual cycle.

As a specific inhibitor of prolactin secretion, Bromocriptine can be used to prevent or suppress physiological lactation, as well as to treat pathological conditions caused by hypersecretion of prolactin.

In amenorrhea and/or anovulatory menstrual cycles (with or without galactorrhea), Bromocriptine can be used to restore the menstrual cycle and ovulation.

When using bromocriptine, the usual measures used to suppress lactation, such as fluid restriction, are not required. Furthermore, Bromocriptine does not affect postpartum uterine involution and does not increase the risk of thromboembolism. Bromocriptine inhibits the growth or reduces the volume of prolactin-secreting pituitary adenomas (prolactinomas).

In patients with acromegaly, in addition to reducing plasma GH and prolactin concentrations, Bromocriptine has a beneficial effect on the clinical manifestations of acromegaly and glucose tolerance.

Bromocriptine reduces the clinical manifestations of polycystic ovary syndrome (PCOS) by restoring normal secretion of luteinizing hormone.

Neurological properties

Due to its dopaminergic activity when used in higher doses compared to those used for endocrinological indications, Bromocriptine is effective in patients with Parkinson’s disease. This disease is characterized by a deficiency of dopamine in the striatum and substantia nigra of the brain. Stimulation of dopamine receptors by bromocriptine in this condition can restore the neurochemical balance in this area of the brain.

Clinically, Bromocriptine reduces the severity of tremor, rigidity, bradykinesia and other symptoms of parkinsonism at all stages of the disease. The therapeutic effect usually persists for many years (good results were noted with therapy duration up to 8 years). Bromocriptine can be prescribed as monotherapy or in combination with other antiparkinsonian drugs, both at the beginning and at later stages of the disease.

Combination with levodopa leads to an increase in the antiparkinsonian effect, which allows for a reduction in the dose of levodopa. Bromocriptine is particularly suitable for patients who experience a worsening response to levodopa or complications such as abnormal involuntary movements (choreoathetoid dyskinesia and/or painful dystonia), end-of-dose deterioration and the “on-off” phenomenon.

Bromocriptine reduces the severity of depressive symptoms often observed in patients with Parkinson’s disease. This is due to its inherent antidepressant properties, confirmed in controlled clinical studies in patients with endogenous or psychogenic depression without Parkinson’s disease.

The prolactin-lowering effect develops within 1-2 hours after taking the drug, reaching a maximum (i.e., a decrease in plasma prolactin levels by more than 80%) after 5-10 hours, and remains close to the maximum for 8-12 hours.

Pharmacokinetics

Absorption

After oral administration, Bromocriptine is well absorbed. In healthy volunteers after oral administration of bromocriptine in tablet form, the half-absorption period of bromocriptine is 0.2-0.5 hours, and C_max in plasma is reached after 1-3 hours. When bromocriptine is taken orally at a dose of 5 mg, C_max is 0.465 ng/ml.

Distribution

Plasma protein binding is 96%.

The prolactin-lowering effect develops within 1-2 hours after taking the drug, reaching a maximum (i.e., a decrease in plasma prolactin levels by more than 80%) after 5-10 hours, and remains close to the maximum for 8-12 hours.

Metabolism

Bromocriptine undergoes active biotransformation during the “first pass” through the liver, which is reflected in a complex metabolite profile and the almost complete absence of the parent substance in urine and feces. It demonstrates high affinity for CYP3A, and the main metabolic pathway is hydroxylation of the proline ring of the cyclopeptide molecule. Consequently, it can be expected that inhibitors and/or potent substrates of CYP3A4 are capable of inhibiting the elimination of bromocriptine and leading to an increase in its plasma concentration. Bromocriptine is also a strong inhibitor of CYP3A4 with a calculated IC₅₀ value of 1.6 µM. However, given the low therapeutic concentrations of free bromocriptine in patients, significant impairment of the metabolism of a concomitantly administered drug, the clearance of which is mediated by CYP3A4, is not expected.

Excretion

The elimination of unchanged bromocriptine from plasma is biphasic with a terminal T_1/2 of about 15 hours (ranging from 8 to 20 hours). Bromocriptine and its metabolites are almost completely excreted in the bile, with only 6% of the dose excreted by the kidneys.

Pharmacokinetics in specific patient groups

Elderly patients (over 65 years). There is no indication that old age has a direct effect on the pharmacokinetic properties and tolerability of bromocriptine.

Patients with hepatic impairment. In patients with impaired liver function, the elimination rate of the drug may slow down and its plasma levels may increase, requiring adjustment of the drug dose.

Indications

Bromocriptine-Richter is indicated for use in adults, children and adolescents aged 7 years and older.

• Suppression of lactation for medical reasons

To prevent or suppress physiological lactation in the postpartum period only for medical reasons (for example, in case of intrapartum fetal death, neonatal death, maternal HIV infection).

It is not recommended to use Bromocriptine for the purpose of suppressing lactation in routine practice or to relieve symptoms of postpartum pain and painful breast engorgement, for which non-pharmacological methods (firm breast support, cold compresses) and/or analgesics can be successfully used.

• Hyperprolactinemia

For the treatment of hyperprolactinemia in patients with hypogonadism and/or galactorrhea.

• Menstrual cycle disorders, female infertility

In the treatment of female infertility in patients with normal basal gonadotropin levels and hyperprolactinemia (absolute or relative).

• Prolactinomas

In a number of specialized departments, Bromocriptine is successfully used in patients with prolactin-secreting adenomas. In particular, Bromocriptine can be considered as a first-line drug in patients with macroadenomas and an alternative to surgery (transsphenoidal hypophysectomy) in patients with microadenomas.

• Acromegaly

Bromocriptine is used in a number of specialized departments as an adjunct in combination with surgery and/or radiation therapy to reduce the concentration of growth hormone in the systemic circulation in the treatment of patients with acromegaly.

• Parkinson’s disease

In the treatment of idiopathic Parkinson’s disease, Bromocriptine is used both as monotherapy and in combination with levodopa in previously untreated patients and in patients with the “on-off” phenomenon. In some cases, the use of bromocriptine may be effective in patients who do not respond to or do not tolerate treatment with levodopa preparations, as well as when the effectiveness of levodopa decreases.

There is insufficient evidence of the effectiveness of bromocriptine in the treatment of premenstrual syndrome and benign breast neoplasms. Therefore, the use of the drug Bromocriptine-Richter in patients with this pathology is not recommended.

ICD codes

Dosage Regimen

For oral administration.

Bromocriptine-Richter tablets should always be taken with food.

The maximum daily dose should not exceed 30 mg.

Adults

Bromocriptine treatment is used for a number of very heterogeneous diseases, for this reason the recommended regimens differ. For most indications, regardless of the final dose, the optimal response with a minimum of side effects is usually achieved by gradually increasing the dose of bromocriptine.

The following scheme is recommended: initial dose – half a tablet (1.25 mg) at bedtime, after 2-3 days the dose should be increased to 2.5 mg at bedtime. Then the dose can be increased by half a tablet or a whole tablet (1.25-2.5 mg) at intervals of 2-3 days, until a maximum dose of 2.5 mg 2 times/day is reached. Further dose increases, if necessary, should be carried out in a similar manner.

Prevention of lactation

At a dose of 2.5 mg on the day of delivery, then 2.5 mg 2 times/day for 14 days. Gradual dose increase of bromocriptine when prescribed for this indication is not required.

Cessation of lactation

At a dose of 2.5 mg on the first day, with an increase in dose after 2-3 days to 2.5 mg 2 times/day for 14 days. Gradual dose increase of bromocriptine when prescribed for this indication is not required.

Hypogonadism/galactorrhea syndromes/infertility

The dose of bromocriptine is gradually increased according to the proposed scheme.

In most patients with hyperprolactinemia, an adequate effect is achieved from the use of the drug at a dose of 7.5 mg/day (in divided doses), but doses up to 30 mg/day can also be used. In female patients with infertility without elevated serum prolactin levels, the usual dose is 2.5 mg 2 times/day.

Prolactinomas

The dose of bromocriptine is gradually increased according to the proposed scheme. Then the dose can be increased by 2.5 mg/day at intervals of 2-3 days with administration according to the following scheme: 2.5 mg – every 8 hours, 2.5 mg – every 6 hours, 5 mg – every 6 hours.

Acromegaly

The dose of bromocriptine is gradually increased according to the proposed scheme. Then the dose can be increased by 2.5 mg/day at intervals of 2-3 days with administration according to the following scheme: 2.5 mg – every 8 hours, 2.5 mg – every 6 hours, 5 mg – every 6 hours.

Parkinson’s disease

Treatment with bromocriptine should be started gradually according to the following scheme

• Week 1: 1.25 mg at bedtime.
• Week 2: 2.5 mg at bedtime.
• Week 3: 2.5 mg 2 times/day.
• Week 4: 2.5 mg 3 times/day.

Then the drug should be taken 3 times/day, increasing the dose by 2.5 mg every 3-14 days depending on the patient’s response. The dose increase should be continued until the optimal dose is reached. The usual optimal dose is from 10 to 30 mg per day. If the patient is already taking levodopa, the dose of levodopa can be gradually reduced and the dose of bromocriptine increased until an optimal balance is achieved.

Special patient groups

Children. Bromocriptine should not be used in children and adolescents under 7 years of age due to the risk associated with safety and efficacy concerns.

Elderly patients (over 65 years). There is no evidence that Bromocriptine poses a special risk for elderly individuals.

Patients with hepatic impairment. In patients with impaired liver function, the elimination rate of the drug may slow down and its plasma concentration may increase, requiring adjustment of the drug dose.

Adverse Reactions

Adverse reactions are presented according to the MedDRA system organ classification, and also according to the frequency of occurrence: common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (<1/10000).

Description of selected adverse reactions

The use of bromocriptine for the purpose of suppressing physiological lactation in the postpartum period has been associated with rare cases of arterial hypertension, myocardial infarction, convulsions, stroke or mental disorders.

Impulse control disorders

Patients receiving treatment with dopamine agonists, including Bromocriptine, may experience pathological gambling, increased libido, hypersexuality, compulsive spending or shopping addiction, constant need to eat and compulsive overeating.

Contraindications

• Hypersensitivity to bromocriptine, or ergot alkaloids, or any excipient of the drug;
• Uncontrolled arterial hypertension;
• Arterial hypertension during pregnancy and in the postpartum period;
• Toxemia of the second half of pregnancy (including preeclampsia and eclampsia).
• Postpartum period in women with a history of severe cardiovascular diseases;
• Coronary artery disease and other severe diseases of the cardiovascular system;
• History of cerebrovascular diseases;
• Obliterating endarteritis;
• Raynaud’s syndrome;
• Temporal arteritis;
• Ulcerative diseases of the gastrointestinal tract and gastrointestinal bleeding;
• Severe hepatic insufficiency;
• Sepsis;
• Severe mental disorders (including in history);
• Tobacco abuse;
• Concomitant use with methylergometrine or other ergot alkaloids, moderate or potent cytochrome P450 inhibitors (for example, itraconazole, voriconazole, clarithromycin);
• Children under 7 years of age (safety and efficacy of bromocriptine use in children under 7 years of age has not been confirmed);
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

With caution

• Use in children over 7 years and adolescents under 18 years;
• Use in patients over 65 years;
• Use in patients with cardiovascular diseases (for example, with arterial hypertension, arrhythmias, history of myocardial infarction);
• Parkinson’s disease (with long-term treatment with high doses of the drug);
• Impaired liver function;
• Severe renal failure;
• Pregnancy (in patients with pituitary adenoma);
• Postpartum period;
• Particular caution should be exercised when using the drug Bromocriptine-Richter in the postpartum period in patients with arterial hypertension who have recently taken vasoconstrictor drugs (sympathomimetics or ergot alkaloids, for example, ergometrine or methylergometrine);
• Concomitant use with antihypertensive therapy;
• Concomitant use with antifungal drugs of the azole group, HIV protease inhibitors.

Use in Pregnancy and Lactation

Pregnancy

In patients wishing to become pregnant, bromocriptine, like all other medicines, should be discontinued upon confirmation of pregnancy, except in cases where it is necessary to continue therapy for medical reasons. When bromocriptine was discontinued after confirmation of pregnancy, no increase in the frequency of premature termination of pregnancy was observed. Clinical experience shows that the use of bromocriptine during pregnancy does not have an adverse effect on the course and outcome of pregnancy.

If pregnancy occurs in women with a pituitary adenoma and bromocriptine treatment is discontinued, careful monitoring of patients throughout the entire pregnancy is necessary. If signs of significant prolactinoma enlargement appear, such as headaches or visual field disturbances, bromocriptine treatment should be resumed or the possibility of surgical intervention should be considered.

Breastfeeding period

Since Bromocriptine suppresses lactation, it should not be prescribed to women who are breastfeeding.

Fertility

When treated with bromocriptine, reproductive function may be restored. Women of childbearing age not planning pregnancy should be advised to use a reliable method of contraception.

Use in Hepatic Impairment

The drug should be used with caution in patients with impaired liver function.

Use of bromocriptine is contraindicated in severe hepatic insufficiency (Child-Pugh class C).

Use in Renal Impairment

The drug should be used with caution in patients with severe renal insufficiency.

Pediatric Use

The use of the drug is contraindicated in children under 7 years of age (safety and efficacy of bromocriptine use in children under 7 years of age has not been established).

The drug should be used with caution in children over 7 years of age and adolescents under 18 years of age.

Geriatric Use

The drug should be used with caution in patients over 65 years of age.

Special Precautions

In women with pathology not associated with hyperprolactinemia, Bromocriptine should be prescribed at the lowest effective therapeutic dose necessary to relieve symptoms. This is important to prevent a decrease in plasma prolactin concentration below normal, leading to impaired corpus luteum function.

Several cases of gastrointestinal bleeding and gastric ulcer have been reported. In such situations, Bromocriptine should be discontinued. Patients with signs of gastric and duodenal ulcers or a history of such disease require careful monitoring during treatment.

Postpartum women

In women receiving Bromocriptine to suppress lactation in the postpartum period, serious adverse events, including arterial hypertension, myocardial infarction, convulsions, stroke, or mental disorders, were rarely reported. In some patients, the development of convulsions or stroke was preceded by severe headache and/or transient visual disturbances. Blood pressure should be carefully monitored, mainly in the first days of taking the drug.

In case of arterial hypertension, chest pain indicating heart disease, severe, progressive or continuous headache (with or without visual impairment) or signs of toxic CNS damage, bromocriptine treatment should be discontinued and the patient should be examined immediately.

Special attention should be paid to patients who are receiving concomitant therapy or have recently received drugs that can change blood pressure, such as vasoconstrictor drugs like sympathomimetics or ergot alkaloids, including ergometrine or methylergometrine. Despite the lack of clear evidence of interaction between bromocriptine and these drugs, their concomitant use in the postpartum period is not recommended.

Prolactin-secreting adenomas

Since patients with pituitary macroadenomas may have concomitant hypopituitarism due to compression or destruction of pituitary tissue, a complete assessment of pituitary function and adequate replacement therapy should be performed before prescribing bromocriptine. In patients with secondary adrenal insufficiency, replacement therapy with corticosteroids is mandatory.

Changes in tumor size should be carefully monitored in patients with pituitary macroadenomas, and if there are signs of tumor growth, the advisability of surgical intervention should be considered.

If a patient with an adenoma becomes pregnant after taking bromocriptine, careful monitoring of the patient is mandatory. Prolactin-secreting adenomas may increase in size during pregnancy. In such patients, treatment with bromocriptine often leads to a reduction in tumor size and rapid restoration of narrowed visual fields. In severe cases, compression of the optic or other cranial nerves may require emergency pituitary surgery.

Visual field impairment is a known complication of macroprolactinoma. Effective treatment with bromocriptine leads to a reduction in tumor size and the severity of hyperprolactinemia, and often to the disappearance of visual disturbances. However, some patients may later develop secondary deterioration of visual fields, despite normalized prolactin levels and reduced tumor size, which may be the result of traction of the optic chiasm, which is pulled down into the partially empty sella turcica.

In these cases, the visual field defect may decrease while taking bromocriptine at a reduced dose, despite some increase in prolactin levels and some re-enlargement of the tumor. Thus, monitoring of visual fields in patients with macroprolactinoma is recommended for early detection of secondary visual field loss due to herniation and for individual selection of the bromocriptine dose.

Some patients with prolactin-secreting adenomas treated with bromocriptine experienced cerebrospinal fluid rhinorrhea. Available data indicate that this phenomenon may occur due to a reduction in the size of an invasive tumor.

Parkinson’s disease

In patients receiving Bromocriptine, isolated cases of pleural and pericardial effusion, as well as pleural and pulmonary fibrosis and constrictive pericarditis, have been reported. Patients with unexplained pleuropulmonary disorders should be thoroughly examined and, if necessary, bromocriptine therapy should be discontinued.

In several patients receiving Bromocriptine, especially in high doses or for a long time, retroperitoneal fibrosis may develop. To promptly recognize retroperitoneal fibrosis at an early reversible stage, it is recommended to monitor its manifestations (such as back pain, swelling of the lower extremities, impaired renal function) in this category of patients.

Bromocriptine should be discontinued if fibrotic changes in the retroperitoneal space are diagnosed or suspected.

Sudden sleep episodes

The use of bromocriptine may be accompanied by drowsiness and episodes of sudden sleep onset, especially in patients with Parkinson’s disease. Sudden falling asleep during daily activities, in some cases without any precursors or warning signs, has been reported very rarely. Patients should be informed about the possibility of such a phenomenon and advised to refrain from driving vehicles or operating machinery while being treated with bromocriptine.

Patients who experience drowsiness and/or episodes of sudden sleep onset should refrain from driving vehicles or operating machinery. Furthermore, the advisability of dose reduction or treatment discontinuation should be considered.

Impulse control disorders

Patients should be regularly monitored for the development of impulse control disorders. Patients and caregivers should be aware of the possibility of patients receiving dopamine agonists (including the drug Bromocriptine-Richter) developing behavioral symptoms of impulse control disorders, including pathological gambling, increased libido, heightened sexual activity, pathological spending or shopping addiction, constant need for food and uncontrolled overeating. If such symptoms develop, the advisability of dose reduction/gradual withdrawal of the drug should be considered.

Use in children and adolescents (7-17 years)

The safety and efficacy of bromocriptine use in children have been established only for prolactinoma and acromegaly – in patients aged 7 years and older. Data on the use of bromocriptine in children under 7 years of age are limited. However, according to other clinical data, including post-marketing reports of adverse events, no difference in drug tolerance between adults and adolescents or children has been identified.

Even in the absence of differences in the adverse reaction profile in children taking Bromocriptine, the possibility of increased sensitivity in them cannot be unequivocally ruled out, so dose titration should be performed in such patients.

Elderly patients

Clinical studies of bromocriptine included an insufficient number of patients aged 65 years and older to determine the presence of differences in response between elderly and younger patients. However, according to other clinical data, including post-marketing reports of adverse events, no difference in response or tolerance in elderly patients compared to patients under 65 years of age has been identified.

Even in the absence of differences in efficacy or the profile of adverse events in elderly patients taking Bromocriptine, the possibility of increased sensitivity in some elderly patients cannot be unequivocally ruled out. In general, the selection of a dose for elderly patients should be approached with caution, starting with the minimum doses, since in this population, impaired liver, kidney, or heart function, concomitant diseases, or concomitant medication use are observed more frequently.

Excipients

The drug contains lactose monohydrate. Patients with rare hereditary diseases such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome should not take this drug.

Effect on ability to drive vehicles and operate machinery

When using the drug, especially in the first days of treatment, hypotensive reactions may be observed, which lead to decreased concentration. Consequently, special caution should be exercised when driving vehicles and operating machinery.

Patients taking Bromocriptine who develop drowsiness and/or episodes of sudden sleep onset should refrain from driving vehicles and not engage in activities that, with reduced concentration, could pose a risk of serious injury or death (e.g., operating machinery) until such episodes and drowsiness have resolved.

Overdose

In all cases of bromocriptine overdose, patients survived; the maximum single oral dose taken to date is 325 mg.

Symptoms nausea, vomiting, dizziness, decreased blood pressure, orthostatic hypotension, tachycardia, drowsiness, lethargy and hallucinations.

Treatment gastric lavage (if the drug was taken very recently), administration of activated charcoal, symptomatic therapy. Metoclopramide may be indicated for the treatment of vomiting or hallucinations.

Children

There are isolated reports of children accidentally taking Bromocriptine. Among the observed adverse events were vomiting, drowsiness and fever. Overdose symptoms resolve within a few hours on their own or after symptomatic therapy.

Drug Interactions

When used concomitantly with macrolide antibiotics, for example, erythromycin or josamycin, the plasma concentration of bromocriptine increases.

Concomitant use of octreotide and bromocriptine in patients with acromegaly is accompanied by an increase in the plasma concentration of the latter.

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

Sympathomimetics, for example, phenylpropanolamine, isometheptene, increase the risk of toxicity.

Bromocriptine should not be used concomitantly with ergot alkaloids.

Bromocriptine is both a substrate and an inhibitor of the cytochrome P450 system (isoenzyme CYP3A4). Therefore, caution should be exercised when bromocriptine is used concomitantly with potent inhibitors or substrates of CYP3A4 (antifungal drugs of the azole group, HIV protease inhibitors).

The tolerance of bromocriptine may decrease while taking alcohol.

Storage Conditions

The drug should be stored in the original packaging (vial in a carton), in a place inaccessible to children, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.