Cabergoline

Cabergoline is a Hyperprolactinemia Agent belonging to the Dopamine (D2) Agonist class.

Cabergoline is approved for treating hyperprolactinemia, a condition characterised by increased prolactin levels in the blood. It is also used to treat disorders related to excessive prolactin production, such as prolactinomas and certain menstrual irregularities.

Cabergoline is well-absorbed orally, with peak plasma levels reached in 2-3 hours. It has a long half-life of about 63-68 hours due to extensive tissue distribution. Metabolism occurs mainly in the liver. Cabergoline is excreted primarily in the faeces, with a smaller portion eliminated in urine.

Headaches, dizziness, nausea, and low blood pressure are some of the most common side effects of cabergoline.

Cabergoline is available in the form of oral Tablets.

The 7-transmembrane G-protein coupled dopamine D2 receptor is connected to Gi proteins. Inhibiting adenylyl cyclase in lactotrophs results in activation of dopamine D2, which lowers intracellular cAMP levels and prevents IP3-dependent release of Ca2+ from intracellular reserves. Instead of inhibiting adenylyl cyclase, calcium levels in the cells may be decreased by blocking calcium input through voltage-gated calcium channels. Additionally, receptor activation prevents p42/p44 MAPK phosphorylation and lowers MAPK/ERK kinase phosphorylation. The c-Raf and B-Raf-dependent inhibition of MAPK/ERK kinase is the mechanism by which MAPK is inhibited. Instead of via adenylyl cyclase inhibition, the release of growth hormone from the pituitary gland is induced by dopamine. This release is mediated by reduced intracellular calcium influx through voltage-gated calcium channels. Improvements in coordinated muscular action are seen in people with movement problems when dopamine D2 receptors in the nigrostriatal pathway are stimulated. The dopamine receptor agonist cabergoline has a long half-life and a strong affinity for D2 receptors. According to receptor-binding tests, cabergoline has a modest affinity for the 5-HT1 and 5-HT2 serotonin receptors and the dopamine D1, 1, and 2 adrenergic receptors.

The Onset of action of Cabergoline typically begins within 3-4 hours after ingestion.

The Duration of Action for Cabergoline in the body is approximately 7 to 28 days.

The Tmax of Cabergoline was found approximately 2 to 3 hours following oral administration.

Cabergoline is available in Tablets

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

As the physician recommends, take the medication orally

once daily, generally with or without a meal.

• Cabergoline treats hyperprolactinemic disorders, either idiopathic or due to prolactinoma (prolactin-secreting adenomas).
• Cabergoline may be used as an adjunct therapy in managing Parkinson's disease.
• Cabergoline may be prescribed to prevent or cease breast milk production, especially after stillbirth, abortion, or in medical situations where breastfeeding is contraindicated.
• Cabergoline may also be prescribed off-label for conditions such as acromegaly (excess growth hormone production), certain types of pituitary tumours, and other dopaminergic-related disorders.

In Treatment of High levels of prolactin

The hormone prolactin stimulates milk production in females and helps in the growth and development of the breasts. In females who have experienced a stillbirth, miscarriage, or abortion, cabergoline helps prevent breast milk production. Dopamine, which causes these elevated levels of prolactin, is acted upon by this substance, which contains milk production.

Cabergoline is approved for use in the following clinical indications:

To treat hyperprolactinemic diseases that are idiopathic or caused by prolactinoma (adenomas that secrete prolactin).

It may also be used as a monotherapy during the initial symptomatic management Or as an adjunct to Levodopa therapy during advanced stages of the disease to manage symptoms of Parkinsonian Syndrome.

Orally: Cabergoline is available as a tablet that can be taken orally. Cabergoline should be swallowed as a whole with a drink of water. It should be taken on an empty stomach or with food to improve its absorption and reduce the likelihood of gastrointestinal side effects. It is best to take it regularly at a fixed time each day following the physician's prescribed schedule for regular and evenly spaced intervals because the dose and duration of therapy are individualized per specific conditions to achieve the most effective and successful treatment outcome.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Tablets: 0.25 mg, 0.5 mg

Cabergoline is available in the form of Oral Tablets

Dose Adjustment in Adult Patients:

Hyperprolactinemia

It is recommended for hyperprolactinemic diseases that can either be idiopathic or have a pituitary adenoma as their source.

Initial dose: 0.25 mg PO twice weekly

Increase by 0.25 mg every four weeks (or longer) up to 1 mg twice weekly.

Cabergoline should be used in treating hyperprolactinemic diseases, along with appropriate dietary restrictions.

While taking Cabergoline, avoid consumption of a high-salt or high-sodium in the diet and be cautious of high-sodium processed foods.

Avoid the consumption of grapefruit or its juice as it may interact with Cabergoline, potentially affecting its absorption and effectiveness.

Taking Cabergoline with a high-fat meal (High-Protein Meals) may delay its absorption and reduce its effectiveness. Taking the medication with a light meal or on an empty stomach is generally recommended.

Limit alcohol consumption while using Cabergoline, as it can enhance the side effects of this medication, including dizziness and drowsiness.

It is advised to stay hydrated, maintain a rich, balanced diet low in saturated fats and cholesterol, and consume plenty of vegetables, whole grains, fruits, and lean proteins to promote overall health and support the medication's effectiveness.

The dietary restriction should be individualized as per patient requirements.

Cabergoline may be contraindicated in the following conditions:-

• Known hypersensitivity to cabergoline, ergot derivatives, or any component of the formulation;
• Uncontrolled hypertension; history of cardiac valvular disorders (indicated by valvopathy of any valve, thickening of valve leaflet, valve restriction, or mixed valve restriction stenosis);
• History of pericardial, pulmonary, or retroperitoneal fibrotic disorders
• Concomitant use with dopamine antagonists

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

Cardiac valvulopathy: Every patient should have a cardiovascular assessment, including an echocardiography, to check for valvular disease. Cabergoline should not be administered to a patient with valvular disease.

To treat hyperprolactinemic diseases, doctors should administer the lowest dose of cabergoline possible. They should also frequently reevaluate if cabergoline medication is still necessary. The risk of cardiac valvulopathy should be evaluated by clinical and diagnostic monitoring (such as a chest x-ray, CT scan, and cardiac echocardiography) after treatment. Regular echocardiographic monitoring is advised every 6 to 12 months or as clinically indicated in the presence of signs and symptoms, including a new cardiac murmur, dyspnea,oedema, or congestive heart failure (CHF).

If an echocardiography indicates new valvular regurgitation, valvular constriction, or thickening of the valve leaflets, cabergoline should be stopped.

In individuals exposed to other drugs associated with valvulopathy, cabergoline should be taken with caution.

• Extracardiac Fibrotic Reactions: Cabergoline has been associated with post-marketing reports of pericardial, retroperitoneal, and pleural fibrosis. Particularly in individuals with a history of extracardiac or cardiac fibrotic diseases, caution is suggested. It's critical to keep an eye out for respiratory symptoms, renal problems, and cardiac manifestations, as well as other indicators of increasing fibrosis. Before beginning cabergoline medication and during it, routine clinical and diagnostic evaluations should be established, including measures of serum creatinine and chest x-rays. Cabergoline withdrawal has been seen to relieve symptoms in patients with pleural effusion or pulmonary fibrosis.

• CNS depression: May cause drowsiness, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (e.g., operating machinery or driving).

• Pleural/retroperitoneal fibrosis: Pleural, pericardial, and retroperitoneal fibrosis cases have been reported. Do not use in patients with a history of cardiac or extracardiac fibrotic disorders. Following diagnosis of fibrosis, discontinuation of cabergoline may result in improvement of the condition.

Postpartum Lactation Inhibition or Suppression: Cabergoline is not recommended for physiologic lactation suppression or inhibition. Another dopamine agonist used for this purpose, bromocriptine, has been associated with hypertension, stroke, and seizures.

• Psychiatric disorders: Aggression, psychotic behaviour, and impulse control disorders such as pathological gambling, increased libido, hypersexuality, compulsive spending or buying, and binge-eating have been reported with use; generally reversible with dose reduction or treatment discontinuation.

Disease-related concerns:

• Hepatic impairment: Use caution and carefully monitor patients with hepatic impairment and extensive hepatic metabolism.

• Peptic ulcer disease: Use caution in patients with peptic ulcer disease (PUD) or GI bleeding.

• Raynaud syndrome: Use with caution in patients with Raynaud syndrome.

Caution is advised when consuming alcohol with Cabergoline

Unsafe to use during breastfeeding. Limited human data suggests the drug may pass into the breastmilk and harm the baby.

Unsafe to use during pregnancy

Avoid consuming foods or beverages like caffeine foods high in tyramine content, such as aged cheeses, cured meats, and alcohol.

The adverse reactions related to Cabergoline can be categorized as

Common Adverse Effects: Mazzotti reaction (e.g. lymphadenitis, oedema, arthralgia, synovitis, tachycardia, fever, pruritus, urticaria) and ophthalmic reaction, particularly in patients undergoing treatment for onchocerciasis; transient aggravation of rosacea

Less Common Adverse effects: Asthenia, fatigue, Conjunctival haemorrhage (if treated for onchocerciasis); conjunctivitis, ocular hyperaemia, eye irritation

Rare Adverse effects: skin burning sensation, irritation, pruritus, dry skin

Reports on Postmarketing

Hypersexuality, increased libido, and pathological gambling are hallmarks of impulse control and compulsive behaviour.

The clinically relevant drug interactions of Cabergoline are briefly summarized here.

Ergot Alkaloids: Concurrent use of Cabergoline with ergot alkaloids (e.g., ergotamine) should be avoided as it may increase the risk of ergotism, a serious condition characterized by vascular constriction.

Dopamine Antagonists: Combining Cabergoline with other dopamine antagonists, such as antipsychotic drugs, may lead to decreased effectiveness or increased side effects.

CYP3A4: Cabergoline may inhibit the enzyme CYP3A4, which plays a role in metabolizing various drugs. When taken with medications metabolized by CYP3A4, it can affect their blood levels.

The common side of Cabergoline includes the following

• Nausea
• Constipation
• Dizziness
• Fatigue
• Headache
• Vomiting
• Vertigo
• stomach ache
• Breast discomfort
• Sleepiness
• Disorders associated with valvulopathy
• Dyspepsia
• Gastritis
• Weakness
• Depression
• Low blood pressure, or postural hypotension
• cold flashes

• Pregnancy

Teratogenic Effects: Category B Could be acceptable.

Either no danger has been shown by animal research, but human studies have yet to be conducted, or some risk has been established by animal studies but not by human studies.

Cabergoline has been used in investigations on reproduction in mice, rats, and rabbits when gavaged.

In rats administered cabergoline at dosages up to 8 mg/kg/day (about 55 times the maximum dose advised for humans), there were maternotoxic effects but no teratogenic effects.

During organogenesis in rats, a dosage of 0.012 mg/kg/day (about 1/7 the highest dose advised for humans) increased post-implantation embryofetal losses. These losses could be brought on by cabergoline's ability to suppress prolactin in rats. During the rabbit's organogenesis phase, cabergoline induced maternotoxicity, characterised by a loss of body weight and reduced food intake, at daily dosages of 0.5 mg/kg/day (about 19 times the maximum dose advised for humans). During the rabbit's organogenesis, 4 mg/kg/day (about 150 times the highest dose recommended for humans) increased the frequency of many abnormalities. However, in a different rabbit trial, dosages up to 8 mg/kg/day (or around 300 times the highest dose advised for humans) were used without causing any embryofetotoxicity or treatment-related abnormalities.

In rats, from 6 days before parturition and during lactation, dosages of more than 0.003 mg/kg/day (about 1/28 the maximum dose advised for humans) impeded development. They resulted in the death of infants due to decreased milk production.

However, there aren't any sufficient and well-researched studies on pregnant women. This medication should only be taken during pregnancy if necessary because research on animal reproduction is not necessarily indicative of human response.

• Nursing Mothers

The medication may be excreted in human milk, however, this is unknown. Given the fact that many medications are excreted in human milk and that cabergoline has the potential to produce serious adverse effects in nursing infants, a choice should be taken about whether to stop breastfeeding or stop the medication, taking into account the significance of the medication to the mother. Cabergoline shouldn't be used to prevent or suppress normal lactation.

Cabergoline's prolactin-lowering effect makes breastfeeding seem to be affected. Cabergoline should not be administered to postpartum women who are currently nursing or intend to do so due to its interference with lactation.

• Pediatric Use

The safety and effectiveness of cabergoline in pediatric patients have not been established.

• Geriatric Use

There were insufficient elderly participants in cabergoline clinical investigations to determine whether their responses differed from those of younger people. Older and younger patients' attitudes have not been shown to differ in other recorded clinical experiences. In general, choosing a dosage for an aged patient should be careful, typically beginning at the low end of the dosing range. This is because senior patients are more likely to have reduced hepatic, renal, or cardiac function, as well as concurrent illness or other medication therapy, and these factors are more common.

Dose Adjustment in Kidney Impairment Patient:

No dosage adjustments are provided; however, cabergoline pharmacokinetics are not altered in patients with moderate to severe renal impairment.

Dose Adjustment in Hepatic Impairment Patient:

There are no dosage adjustments provided; use with caution and monitor carefully in patients with severe hepatic impairment.

Signs and Symptoms

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Cabergoline. Overconsumption of Cabergoline could lead to symptoms such as nausea, vomiting, confusion, nasal congestion, syncope, or hallucinations.

Management

There is no specific antidote or treatment for excessive intake of Cabergoline. However, immediate medical attention is essential. Cabergoline should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake. Activated charcoal or gastric lavage may also be considered if the overdose is detected shortly after ingestion to reduce absorption.

Management typically involves supportive measures and symptomatic treatment. Symptomatic treatment may include antiemetics for nausea and vomiting, fluids for dehydration, and medications to control blood pressure if it becomes severely elevated.

Pharmacodynamics:

Cabergoline has a variety of pharmacologic effects by stimulating centrally placed dopaminergic receptors. There are two dopaminergic subfamilies and five distinct dopamine receptor types. The D1 and D5 subreceptors of the dopaminergic D1 receptor subfamily are linked to dyskinesias. The D2, D3, and D4 subreceptors of the dopaminergic D2 receptor subfamily are related to the amelioration of movement disorder symptoms. Therefore, the main objectives of dopaminergic antiparkinsonian drugs are agonist activity specific for D2 subfamily receptors, particularly D2 and D3 receptor subtypes. Dopamine agonists are hypothesised to have an antiparkinsonian impact predominantly due to postsynaptic D2 activation, although presynaptic D2 stimulation has neuroprotective benefits. This semi-synthetic ergot derivative has strong agonist effects on the D2- and D3 dopamine receptors.

Additionally, it demonstrates agonist action (in decreasing order of binding affinities) on the 5-hydroxytryptamine (5-HT)2B, 5-HT2A, 5-HT1D, dopamine D4, 5-HT1A, dopamine D1, 5-HT1B, and 5-HT2C receptors and antagonist activity on the 2B, 2A, and 2C receptors. When the brain's nigrostriatal system loses about 80% of its dopaminergic function, Parkinsonian Syndrome becomes apparent. Due to the striatum's role in regulating the intensity of coordinated muscle activity (such as movement, balance, and walking), its loss of function may cause dystonia (acute muscle contraction), Parkinsonism (which manifests as tremor, rigidity, and flattened affect), akathisia (inner restlessness), tardive dyskinesia (involuntary muscle movements typically associated with long-term loss of dopaminergic activity), and neuroleptic malignant syndrome. Hallucinations and delusions are adverse effects of dopamine agonists caused by high dopaminergic activity in the brain's mesolimbic pathway; these symptoms are present in schizophrenia patients with excessive dopaminergic activity in this brain region. It's also possible that 5-HT2A agonism is the cause of the hallucinatory side effects of dopamine agonists. The hypothalamus is the starting point of the brain's tuberoinfundibular pathway, leading to the pituitary. Dopamine blocks prolactin secretion in this route by lactotrophs in the anterior pituitary. Prolactin production in the tuberoinfundibular pathway is inhibited by increased dopaminergic activity.

Pharmacokinetics:

• Absorption

Within 2-3 hours after giving 12 healthy adult volunteers, a single oral doses of 0.5 to 1.5 mg, cabergoline's mean peak plasma levels of 30 to 70 picograms/mL (pg/mL) were seen. In 12 healthy adult volunteers and 9 adult Parkinsonian patients, cabergoline plasma levels were dose-proportional across the 0.5 to 7 mg dosing range. A once-weekly dosage regimen is likely to result in steady-state levels two to three times greater than those resulting from a single dose, according to repeat-dose research in 12 healthy volunteers. Cabergoline is not known to have a 100% bioavailability. There is a first-pass impact on a sizeable portion of the delivered dosage. According to 12 healthy participants' urine data, cabergoline's elimination half-life was between 63 and 69 hours. Due to cabergoline's long half-life and slow elimination, its prolactin-lowering impact may last long.

Half-life:63-69 hr

• Distribution

According to total radioactivity, cabergoline (and/or its metabolites) has an extensive tissue distribution in animals. Pituitary radioactivity has a half-life of around 60 hours and is eliminated more than 100 times faster than radioactivity in plasma. This result is consistent with the drug's sustained reduction in prolactin. Studies using whole-body autoradiography on pregnant rats revealed negligible foetal absorption but significant amounts in the uterine wall. The presence of considerable radioactivity (parent plus metabolites) in lactating rats' milk raises the possibility of exposure to nursing babies. The medication has a wide geographic distribution in the body. Human plasma proteins are moderately bound (40% to 42%) but concentration-independently bound to cabergoline. It is unlikely that its disposition will be affected by the concurrent dosage of highly protein-bound medications.

Protein Bound: 40-42%

• Metabolism

The substantial metabolization of cabergoline occurs in humans and animals, mainly by the hydrolysis of the acyl-urea bond or the urea moiety. The metabolism mediated by cytochrome P-450 is relatively low. In rats, cabergoline does not result in enzyme induction or inhibition. The primary metabolites discovered so far do not add to the therapeutic benefit of cabergoline because hydrolysis of the acyl urea or urea moiety eliminates the prolactin-lowering impact of cabergoline.

Peak plasma time: 2-3 hr

Peak Plasma: 30-70 pg/mL following single oral doses of 0.5-1.5 mg

• Excretion

After giving radioactive cabergoline orally to five healthy volunteers, 22% and 60% of the dosage were eliminated in the urine and faeces after 20 days. 4% or less of the dosage was eliminated in urine unaltered. The clearances of cabergoline through the nonrenal and renal systems are 3.2 L/min and 0.08 L/min, respectively. Similar urinary excretion was seen in hyperprolactinemic individuals.

Renal Clearance: 0.08 L/min

Excretion: Urine (22%); feces (60%)

• Ferrari, C et al. “Cabergoline: a new drug for treating hyperprolactinaemia.” Human reproduction (Oxford, England) vol. 10,7 (1995): 1647-52. doi:10.1093/oxfordjournals.humrep.a136149
• Verhelst, J et al. “Cabergoline in the treatment of hyperprolactinemia: a study in 455 patients.” The Journal of Clinical Endocrinology and Metabolism vol. 84,7 (1999): 2518-22. doi:10.1210/jcem.84.7.5810
• Abs, R et al. “Cabergoline in treating acromegaly: a study in 64 patients.” The Journal of Clinical Endocrinology and Metabolism vol. 83,2 (1998): 374-8. doi:10.1210/jcem.83.2.4556
• Alipour, Mohammadesmaeil et al. “Cabergoline in the Treatment of Methamphetamine-Dependent Patients and Its Effect on Serum Level of the Glial Cell-Derived Neurotrophic Factor: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.” European addiction research vol. 27,6 (2021): 457-468. doi:10.1159/000515398

If a patient becomes pregnant, suspects she is pregnant, or plans to get pregnant while receiving treatment, they should be encouraged to tell their physician. If there is any reason to suspect pregnancy, a pregnancy test should be taken, and the patient should talk to their doctor about continuing therapy.

If a patient has swelling in their limbs, a chronic cough, trouble breathing when lying down, or shortness of breath, they should notify a physician immediately.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
• https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e497366b-a124-4d7f-bd45-a883c392d4bb
• https://pubmed.ncbi.nlm.nih.gov/11249538/
• https://www.uhsussex.nhs.uk/resources/cabergoline-treatment/