Bromocriptine

Bromocriptine is a Antidiabetic belonging to pharmacology class of Dopamine Agonist.

Bromocriptine is indicated in the treatment of Diabetes mellitus, type 2, treatment.

Bromocriptine mesylate is a semisynthetic ergot alkaloid derivative with potent dopaminergic activity. It inhibits prolactin secretion and may be used to treat dysfunctions associated with hyperprolactinemia. Bromocriptine is also indicated for the management of signs and symptoms of Parkinsonian Syndrome, as well as the treatment of acromegaly. Bromocriptine has been associated with pulmonary fibrosis, and can also cause sustained suppression of somatotropin (growth hormone) secretion in some patients with acromegaly.

Bromocriptine is available in the form of Tablets, capsules.

The molecule is available in India, USA, Japan, Germany.

The dopamine D₂ receptor is a 7-transmembrane G-protein coupled receptor associated with G_i proteins. In lactotrophs, stimulation of dopamine D₂ receptor causes inhibition of adenylyl cyclase, which decreases intracellular cAMP concentrations and blocks IP3-dependent release of Ca²⁺ from intracellular stores. Decreases in intracellular calcium levels may also be brought about via inhibition of calcium influx through voltage-gated calcium channels, rather than via inhibition of adenylyl cyclase. Additionally, receptor activation blocks phosphorylation of p42/p44 MAPK and decreases MAPK/ERK kinase phosphorylation. Inhibition of MAPK appears to be mediated by c-Raf and B-Raf-dependent inhibition of MAPK/ERK kinase. Dopamine-stimulated growth hormone release from the pituitary gland is mediated by a decrease in intracellular calcium influx through voltage-gated calcium channels rather than via adenylyl cyclase inhibition. Stimulation of dopamine D₂ receptors in the nigrostriatal pathway leads to improvements in coordinated muscle activity in those with movement disorders.

The Tmax of Bromocriptine 1-4 hours.

Bromocriptine is available in Tablets

Oral: Administer without regard to meals.

Bromocriptine can be used in the treatment of Diabetes mellitus, type 2, treatment.

Bromocriptine mesylate is a dopamine receptor agonist, which activates post-synaptic dopamine receptors. The dopaminergic neurons in the tuberoinfundibular process modulate the secretion of prolactin from the anterior pituitary by secreting a prolactin inhibitory factor (thought to be dopamine); in the corpus striatum the dopaminergic neurons are involved in the control of motor function.

Bromocriptine is approved for use in the following specifically clinical indications mentioned below:

Diabetes mellitus, type 2, treatment (Bromocriptine only): To improve glycemic control in adults with type 2 diabetes mellitus as an adjunct to diet and exercise.

Hyperprolactinemic disorders (excluding Bromocriptine): Treatment of prolactin-secreting pituitary adenoma or disorders associated with hyperprolactinemia including amenorrhea with or without galactorrhea, hypogonadism, or infertility.

Parkinson disease (excluding Bromocriptine): Treatment of the signs and symptoms of idiopathic or postencephalitic Parkinson disease; as adjunctive treatment to levodopa and a peripheral decarboxylase inhibitor.

Diabetes mellitus, type 2, treatment:

Note: Agents other than bromocriptine are recommended for treatment of patients with type 2 diabetes mellitus .

Oral: Initial: 0.8 mg once daily in the morning. If additional glycemic control is needed, may increase dose in 0.8 mg increments at weekly intervals as tolerated; usual dose: 1.6 to 4.8 mg once daily (maximum: 4.8 mg/day).

Tablets, Capsule

5 mg, 0.8 mg, 2.5 mg.

Tablets, Capsule.

Dose Adjustment in Kidney impairment patient:

Oral:

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Administer with food to decrease GI distress. Bromocriptine: Administer within 2 hours of waking in the morning. If the morning dose is missed, wait until the next morning and resume with the usual dose. In neuroleptic malignant syndrome, administration via nasogastric tube has been described.

Administration: Pediatric

Administer with food to decrease GI distress.

Bromocriptine may be contraindicated in the following conditions:-

● Serious hypersensitivity (eg, anaphylaxis, angioedema) to Bromocriptine or any component of the formulation

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

Disease-related concerns:

Hypersensitivity to bromocriptine, ergot alkaloids, or any component of the formulation.

Additional product-specific contraindications:

Bromocriptine: Syncopal migraine; postpartum patients; lactating patients.

Parlodel: Uncontrolled hypertension; pregnancy (risk to benefit evaluation must be performed in patients who become pregnant during treatment - hypertension during treatment should generally result in efforts to withdraw); postpartum patients with a history of coronary artery disease or other severe cardiovascular conditions (unless withdrawal of medication is medically contraindicated).

Warnings/Precautions

Concerns related to adverse effects:

• Cardiac valvular fibrosis: Ergot alkaloids and derivatives have been associated with fibrotic valve thickening (eg, aortic, mitral, tricuspid); usually associated with long-term, chronic use.

• Cardiovascular effects: Hypotension, including orthostatic hypotension and syncope, may occur, particularly upon initiation of therapy and dose escalation. In addition, hypertension, seizures, MI, and stroke have been reported. Severe headache or visual changes may precede events. The onset of reactions may be immediate or delayed (often may occur in the second week of therapy). In a scientific statement from the American Heart Association, bromocriptine has been determined to be an agent that may cause direct myocardial toxicity (magnitude: major) (AHA [Page 2016]).

• CNS depression: May cause CNS depression, which may impair physical or mental abilities, and episodes of sudden sleep onset particularly in patients with Parkinson disease; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

• Hallucinations: Visual or auditory hallucinations may occur when administered alone or concomitantly with levodopa; symptoms may persist for several weeks following discontinuation.

• Impulse control disorders: Dopamine agonists used for Parkinson disease or restless legs syndrome have been associated with compulsive behaviors and/or loss of impulse control, which has manifested as new or increased gambling urges, sexual urges, uncontrolled spending, or other intense urges. Dose reduction or discontinuation of therapy reverses these behaviors in some, but not all cases.

• Pleural/retroperitoneal fibrosis: Cases of pleural and pericardial effusions, as well as pleural, pulmonary, and/or retroperitoneal fibrosis and constrictive pericarditis have been reported with prolonged and high-dose daily use. Discontinue therapy if fibrotic changes are suspected.

Disease-related concerns:

Cardiovascular disease: Use with caution in patients with cardiovascular disease (myocardial infarction; residual atrial, nodal, or ventricular arrhythmia).

Dementia: Use with caution in patients with dementia; high doses may be associated with confusion and mental disturbances.

Galactose intolerance/malabsorption (Parlodel): Avoid use in patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.

Hepatic impairment: Use with caution in patients with hepatic impairment.

Macroadenomas: Discontinuation of therapy in patients with macroadenomas has been associated with rapid regrowth of tumor and increased prolactin serum levels.

Peptic ulcer disease: Use with caution in patients with peptic ulcer disease; severe gastrointestinal bleeding has been reported (some fatal).

Prolactin-secreting adenomas: Cerebrospinal fluid rhinorrhea has been observed in some of these patients.

Psychosis: Use with caution in patients with psychosis; dopamine agonists may exacerbate the disorder or diminish the effectiveness of drugs used to treat the disorder. Use in patients with severe psychotic disorder is not recommended.

Dosage form specific issues:

Interchangeability (Bromocriptine): Due to a difference in the formulation and resulting pharmacokinetics of Bromocriptine ("quick-release" tablet) compared to other formulations of bromocriptine, interchangeability with any other bromocriptine product is not recommended in the setting of type 2 diabetes mellitus management.

Other warnings/precautions:

Appropriate use (Bromocriptine): Not indicated for use in type 1 diabetes mellitus or diabetic ketoacidosis.

Discontinuation of therapy: Dopaminergic agents have been associated with a syndrome resembling neuroleptic malignant syndrome on abrupt withdrawal or significant dosage reduction after long-term use; gradual dosage reduction is recommended when discontinuing therapy. Apathy, anxiety, depression, fatigue, insomnia, pain, and sweating have occurred during taper or after discontinuation of therapy, which may not respond well to levodopa. Educate patient on potential of withdrawal symptoms; consider read ministration of a dopamine agonist at the lowest effective dose in patients experiencing symptoms.

Visual monitoring: Rapidly progressing visual field loss requires neurosurgical consultation.

There is no sufficient scientific evidence traceable regarding use and safety of Bromocriptine in concurrent use with alcohol.

Bromocriptine is known to inhibit lactation.

Use is contraindicated in lactating patients when used for the treatment of type 2 diabetes. Use is contraindicated in the postpartum period in patients with a history of coronary artery disease or other severe cardiovascular conditions (unless withdrawal of medication for the treatment of hyperprolactinemic disorders is medically contraindicated).

A previous indication for prevention of postpartum lactation was withdrawn voluntarily by the manufacturer due to safety issues (Woodcock 1995). Adverse events such as hypertension, myocardial infarction, psychosis, seizures, and stroke have been reported in postpartum patients when used to inhibit lactation; these reactions can be severe and life threatening. The incidence of adverse events in increased in patients with underlying risk factors Bromocriptine is not a preferred medication when treatment is needed for use in breastfeeding patients with an overabundant milk supply (hypergalactia)

Pregnancy Category B

Administration of 10-30 mg/kg of bromocriptine to 2 strains of rats on days 6-15 postcoitum (p.c.) as well as a single dose of 10 mg/kg on day 5 p.c. interfered with nidation.

Three mg/kg given on days 6-15 were without effect on nidation, and did not produce any anomalies. In animals treated from day 8-15 p.c., i.e., after implantation, 30 mg/kg produced increased prenatal mortality in the form of increased incidence of embryonic resorption. One anomaly, aplasia of spinal vertebrae and ribs, was found in the group of 262 fetuses derived from the dams treated with 30 mg/kg bromocriptine. No fetotoxic effects were found in offspring of dams treated during the peri- or postnatal period.

Take with or without food.

The adverse reactions related to Bromocriptine can be categorized as:

Common Adverse Effects: Hypoglycemia (particularly in combination with sulfonylureas or insulins); worsening renal function, including acute renal failure (may require dialysis); severe and disabling arthralgia, bullous pemphigoid.

Less Common Adverse effects: Gastrointestinal: Diarrhea, nausea.

Rare Adverse effects: Acute pancreatitis including hemorrhagic or necrotizing pancreatitis, serious hypersensitivity reactions (e.g. anaphylaxis, angioedema, cutaneous vasculitis, exfoliative skin conditions including Stevens-Johnson syndrome).

The clinically relevant drug interactions of Bromocriptine is briefly summarized here

Increased risk of hypoglycemia when co-administered with sulfonylureas (e.g. glipizide, glimepiride) and insulins; consider lowering the dose of insulins or sulfonylureas. May slightly increase the serum concentration of digoxin.

The common side of Bromocriptine include the following

Hypoglycemia (particularly in combination with sulfonylureas or insulins); worsening renal function, including acute renal failure (may require dialysis); severe and disabling arthralgia, bullous pemphigoid.

Pregnancy Category B

Reproduction studies have been performed in rats and rabbits. Doses of Bromocriptine up to 125 mg/kg (approximately 12 times the human exposure at the maximum recommended human dose) did not impair fertility or harm the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., maintains a registry to monitor the pregnancy outcomes of women exposed to Januvia while pregnant. Health care providers are encouraged to report any prenatal exposure to Januvia by calling the Pregnancy Registry at 1-800-986-8999.

Bromocriptine administered to pregnant female rats and rabbits from gestation day 6 to 20 (organogenesis) was not teratogenic at oral doses up to 250 mg/kg (rats) and 125 mg/kg (rabbits), or approximately 30- and 20-times human exposure at the maximum recommended human dose (MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased the incidence of rib malformations in offspring at 1000 mg/kg, or approximately 100 times human exposure at the MRHD.

Bromocriptine administered to female rats from gestation day 6 to lactation day 21 decreased body weight in male and female offspring at 1000 mg/kg. No functional or behavioral toxicity was observed in offspring of rats.

Placental transfer of Bromocriptine administered to pregnant rats was approximately 45% at 2 hours and 80% at 24 hours postdose. Placental transfer of Bromocriptine administered to pregnant rabbits was approximately 66% at 2 hours and 30% at 24 hours.

Labor and Delivery

There is no FDA guidance on use of Bromocriptine during labor and delivery.

Nursing Mothers

Bromocriptine is secreted in the milk of lactating rats at a milk to plasma ratio of 4:1. It is not known whether Bromocriptine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Januvia is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of Januvia in pediatric patients under 18 years of age have not been established.

Geriatric Use

Of the total number of subjects (N=3884) in pre-approval clinical safety and efficacy studies of Januvia, 725 patients were 65 years and over, while 61 patients were 75 years and over. No overall differences in safety or effectiveness were observed between subjects 65 years and over and younger subjects. While this and other reported clinical experience have not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly, and it may be useful to assess renal function in these patients prior to initiating dosing and periodically thereafter.

Gender

There is no FDA guidance on the use of Bromocriptine with respect to specific gender populations.

Race

There is no FDA guidance on the use of Bromocriptine with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Bromocriptine in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Bromocriptine in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Bromocriptine in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance on the use of Bromocriptine in patients who are immunocompromised.

Pharmacodynamics:

Bromocriptine stimulates centrally-located dopaminergic receptors resulting in a number of pharmacologic effects. Five dopamine receptor types from two dopaminergic subfamilies have been identified. The dopaminergic D1 receptor subfamily consists of D₁ and D₅ subreceptors, which are associated with dyskinesias. The dopaminergic D2 receptor subfamily consists of D₂, D₃ and D₄ subreceptors, which are associated with improvement of symptoms of movement disorders. Thus, agonist activity specific for D2 subfamily receptors, primarily D₂ and D₃ receptor subtypes, are the primary targets of dopaminergic antiparkinsonian agents. It is thought that postsynaptic D₂ stimulation is primarily responsible for the antiparkinsonian effect of dopamine agonists, while presynaptic D₂ stimulation confers neuroprotective effects. This semisynthetic ergot derivative exhibits potent agonist activity on dopamine D₂-receptors. It also exhibits agonist activity (in order of decreasing binding affinity) on 5-hydroxytryptamine (5-HT)_1D, dopamine D₃, 5-HT_1A, 5-HT_2A, 5-HT_1B, and 5-HT_2C receptors, antagonist activity on α_2A-adrenergic, α_2C, α_2B, and dopamine D₁ receptors, partial agonist activity at receptor 5-HT_2B, and inactivates dopamine D₄ and 5-HT₇ receptors. Parkinsonian Syndrome manifests when approximately 80% of dopaminergic activity in the nigrostriatal pathway of the brain is lost. As this striatum is involved in modulating the intensity of coordinated muscle activity (e.g. movement, balance, walking), loss of activity may result in dystonia (acute muscle contraction), Parkinsonism (including symptoms of bradykinesia, tremor, rigidity, and flattened affect), akathesia (inner restlessness), tardive dyskinesia (involuntary muscle movements usually associated with long-term loss of dopaminergic activity), and neuroleptic malignant syndrome, which manifests when complete blockage of nigrostriatal dopamine occurs. High dopaminergic activity in the mesolimbic pathway of the brain causes hallucinations and delusions; these side effects of dopamine agonists are manifestations seen in patients with schizophrenia who have overractivity in this area of the brain. The hallucinogenic side effects of dopamine agonists may also be due to 5-HT_2A agonism. The tuberoinfundibular pathway of the brain originates in the hypothalamus and terminates in the pituitary gland. In this pathway, dopamine inhibits lactotrophs in anterior pituitary from secreting prolactin. Increased dopaminergic activity in the tuberoinfundibular pathway inhibits prolactin secretion making bromocriptine an effective agent for treating disorders associated with hypersecretion of prolactin. Pulmonary fibrosis may be associated bromocriptine’s agonist activity at 5-HT_1B and 5-HT_2B receptors.

Pharmacokinetics:

Absorption:Bromocriptine is 28% of the oral dose is absorbed; however due to a substantial first pass effect, only 6% of the oral dose reaches the systemic circulation unchanged. Bromocriptine and its metabolites appear in the blood as early as 10 minutes following oral administration and peak plasma concentration are reached within 1-1.5 hours. Serum prolactin may be decreased within 2 hours or oral administration with a maximal effect achieved after 8 hours. Growth hormone concentrations in patients with acromegaly is reduced within 1-2 hours with a single oral dose of 2.5 mg and decreased growth hormone concentrations persist for at least 4-5 hours.

Distribution: NA

Metabolism: Completely metabolized by the liver, primarily by hydrolysis of the amide bond to produce lysergic acid and a peptide fragment, both inactive and non-toxic. Bromocriptine is metabolized by cytochrome P450 3A4 and excreted primarily in the feces via biliary secretion.

Excretion: Parent drug and metabolites are almost completely excreted via the liver, and only 6% eliminated via the kidney.

1. https://www.uptodate.com/contents/Bromocriptine -drug-information?search=Bromocriptine &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/Bromocriptine _2015-1215.pdf
4. https://www.mims.com/india/drug/info/Bromocriptine ?type=full&mtype=generic#mechanism-of-action