Cabergoline

Cabergoline Ergot Derivative; Hyperprolactinemia Agent, Dopamine (D2) Agonist belonging to pharmacology class of Antidiabetic

Cabergoline is a dopamine receptor agonist used for the treatment of hyperprolactinemic conditions due to various causes.

The dopamine D2 receptor is a 7-transmembrane G-protein coupled receptor associated with Gi proteins. In lactotrophs, stimulation of dopamine D2 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. Cabergoline is a long-acting dopamine receptor agonist with a high affinity for D2 receptors. Receptor-binding studies indicate that cabergoline has low affinity for dopamine D1, α1,- and α2- adrenergic, and 5-HT1- and 5-HT2-serotonin receptors Cabergoline is available in the form of Tablets, , Cream, Lotion.

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

Cabergoline is a long acting dopamine receptor agonist with a high affinity for D₂ receptors; prolactin secretion by the anterior pituitary is predominantly under hypothalamic inhibitory control exerted through the release of dopamine. It is a potent 5-HT_2B-receptor agonist, which may contribute to observed fibrotic/valvulopathic events

The Tmax of Cabergoline 2 to 3 hours.

Onset of Action: Most patients have response to treatment within 2 hours.

Cabergoline is available in Tablets.

Tablet: Administer with meals (may increase tolerability).

Orally-disintegrating tablet: Must be taken whole; do not break, crush, or chew. Place on tongue and allow to dissolve. Administration with liquid is not required.

Cabergoline can be for the treatment of hyperprolactinemic disorders, either idiopathic or due to prolactinoma (prolactin-secreting adenomas). May also be used to manage symptoms of Parkinsonian Syndrome as monotherapy during initial symptomatic management or as an adjunct to levodopa therapy during advanced stages of disease.

Cabergoline is a member of the ivermectin class of broad-spectrum antiparasitic agents which have a unique mode of action. Compounds of the class bind selectively and with high affinity to glutamate-gated chloride ion channels which occur in invertebrate nerve and muscle cells. This leads to an increase in the permeability of the cell membrane to chloride ions with hyperpolarization of the nerve or muscle cell, resulting in paralysis and death of the parasite. Compounds of this class may also interact with other ligand-gated chloride channels, such as those gated by the neurotransmitter gamma-aminobutyric acid (GABA).

Cabergoline is approved for use in the following clinical indications

Hyperprolactinemic disorders: Treatment of hyperprolactinemic disorders, either idiopathic or caused by pituitary adenomas.

ORAI: Administer with meals (may increase tolerability).

Hazardous Drugs Handling Considerations

Hazardous agent Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage. NIOSH recommends single gloving for administration of intact tablets or capsules Assess risk to determine appropriate containment strategy.

Tablets: 0.5 mg

Tablet.

Dose Adjustment in Kidney impairment patient:

There are no dosage adjustments provided in the manufacturer's labeling; however, cabergoline pharmacokinetics are not altered in patients with moderate to severe renal impairment.

Dose Adjustment in Hepatic Patient:

There are no dosage adjustments provided in the manufacturer's labeling; use with caution and monitor carefully in patients with severe hepatic impairment (Child-Pugh class C) (extensive hepatic metabolism).

Take with food.

Cabergoline may be contraindicated in the following conditions:

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

Other warnings/precautions:

Cardiac valvulopathy: Cardiac valvulopathy has been reported with use. Risk is increased with use of high doses (eg, >2 mg/day). Although some conflicting data exist, a majority of observational evidence suggests the risk of valvulopathy in patients receiving typical low dose regimens (eg, ≤2 mg/week) is minimal or absent (Budayr 2020; ES [Katznelson 2014]; ES [Melmed 2011]; Stiles 2021).

Cardiovascular effects: Initial doses >1 mg may cause orthostatic hypotension; may be symptomatic. Use with caution in patients with cardiovascular disease; hypertension, stroke, and seizure have been reported with other dopamine agonists. Concurrent use with antihypertensives may increase risk.

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

Pleural/retroperitoneal fibrosis: Cases of pleural, pericardial, and retroperitoneal fibrosis 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 condition.

Psychiatric disorders: Aggression, psychotic behavior, 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 discontinuation of treatment.

Disease-related concerns:

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

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

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

Alcohol-Cabergoline interaction has not been established. 

It is not known if Cabergoline is present in breast milk following topical application.

Cabergoline is present in breast milk following oral administration. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Use of topical Cabergoline for the treatment of pediculosis pubis or scabies is likely compatible with breastfeeding.

Pregnancy Category B

Reproduction studies have been performed with cabergoline in mice, rats, and rabbits administered by gavage. (Multiples of the maximum recommended human dose in this section are calculated on a body surface area basis using total mg/m2/week for animals and mg/m2/week for a 50 kg human.)

There were maternotoxic effects but no teratogenic effects in mice given cabergoline at doses up to 8 mg/kg/day (approximately 55 times the maximum recommended human dose) during the period of organogenesis.

A dose of 0.012 mg/kg/day (approximately 1/7 the maximum recommended human dose) during the period of organogenesis in rats caused an increase in post-implantation embryofetal losses. These losses could be due to the prolactin inhibitory properties of cabergoline in rats. At daily doses of 0.5 mg/kg/day (approximately 19 times the maximum recommended human dose) during the period of organogenesis in the rabbit, cabergoline caused maternotoxicity characterized by a loss of body weight and decreased food consumption. Doses of 4 mg/kg/day (approximately 150 times the maximum recommended human dose) during the period of organogenesis in the rabbit caused an increased occurrence of various malformations. However, in another study in rabbits, no treatment-related malformations or embryofetotoxicity were observed at doses up to 8 mg/kg/day (approximately 300 times the maximum recommended human dose).

In rats, doses higher than 0.003 mg/kg/day (approximately 1/28 the maximum recommended human dose) from 6 days before parturition and throughout the lactation period inhibited growth and caused death of offspring due to decreased milk secretion.

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.

Increased bioavailability with a high-fat meal.

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 hemorrhage (if treated for onchocerciasis); conjunctivitis, ocular hyperemia, eye irritation

Rare Adverse effects: Skin burning sensation, Irritation, Pruritus, Dry skin.

The clinically relevant drug interactions of Cabergoline is briefly summarized here

Rarely, increased INR with warfarin.

The common side of Cabergoline include the following:

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.

Pregnancy

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cabergoline in women who are pregnant.

Labor and Delivery

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

Nursing Mothers

• It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from cabergoline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Use of cabergoline for the inhibition or suppression of physiologic lactation is not recommended (see PRECAUTIONS section).
• The prolactin-lowering action of cabergoline suggests that it will interfere with lactation. Due to this interference with lactation, cabergoline should not be given to women postpartum who are breastfeeding or who are planning to breastfeed.

Pediatric Use

• Safety and effectiveness of cabergoline in pediatric patients have not been established.

Geriatric Use

• Clinical studies of cabergoline did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Gender

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

Race

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

Renal Impairment

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

Hepatic Impairment

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

Acute Overdose

Signs and Symptoms

Overdosage might be expected to produce nasal congestion, syncope, or hallucinations.

Management

Measures to support blood pressure should be taken if necessary.

Chronic Overdose

There is limited information regarding Chronic Overdose of Cabergoline in the drug label

• Pharmacodynamics:

Dose response with inhibition of plasma prolactin, onset of maximal effect, and duration of effect has been documented following single cabergoline doses to healthy volunteers (0.05 to 1.5 mg) and hyperprolactinemic patients (0.3 to 1 mg). In volunteers, prolactin inhibition was evident at doses > 0.2 mg, while doses ≥ 0.5 mg caused maximal suppression in most subjects. Higher doses produce prolactin suppression in a greater proportion of subjects and with an earlier onset and longer duration of action. In 12 healthy volunteers, 0.5, 1, and 1.5 mg doses resulted in complete prolactin inhibition, with a maximum effect within 3 hours in 92% to 100% of subjects after the 1 and 1.5 mg doses compared with 50% of subjects after the 0.5 mg dose.

In hyperprolactinemic patients (N = 51), the maximal prolactin decrease after a 0.6 mg single dose of cabergoline was comparable to 2.5 mg bromocriptine; however, the duration of effect was markedly longer (14 days vs. 24 hours). The time to maximal effect was shorter for bromocriptine than cabergoline (6 hours vs. 48 hours).

In 72 healthy volunteers, single or multiple doses (up to 2 mg) of cabergoline resulted in selective inhibition of prolactin with no apparent effect on other anterior pituitary hormones (GH, FSH, LH, ACTH, and TSH) or cortisol.

• Pharmacokinetics:

Absorption

Following single oral doses of 0.5 mg to 1.5 mg given to 12 healthy adult volunteers, mean peak plasma levels of 30 to 70 picograms (pg)/mL of cabergoline were observed within 2 to 3 hours. Over the 0.5 to 7 mg dose range, cabergoline plasma levels appeared to be dose-proportional in 12 healthy adult volunteers and nine adult parkinsonian patients. A repeat-dose study in 12 healthy volunteers suggests that steady-state levels following a once-weekly dosing schedule are expected to be two-fold to three-fold higher than after a single dose. The absolute bioavailability of cabergoline is unknown. A significant fraction of the administered dose undergoes a first-pass effect. The elimination half-life of cabergoline estimated from urinary data of 12 healthy subjects ranged between 63 to 69 hours. The prolonged prolactin-lowering effect of cabergoline may be related to its slow elimination and long half-life.

Distribution

In animals, based on total radioactivity, cabergoline (and/or its metabolites) has shown extensive tissue distribution. Radioactivity in the pituitary exceeded that in plasma by > 100 fold and was eliminated with a half-life of approximately 60 hours. This finding is consistent with the long-lasting prolactin-lowering effect of the drug. Whole body autoradiography studies in pregnant rats showed no fetal uptake but high levels in the uterine wall. Significant radioactivity (parent plus metabolites) detected in the milk of lactating rats suggests a potential for exposure to nursing infants. The drug is extensively distributed throughout the body. Cabergoline is moderately bound (40% to 42%) to human plasma proteins in a concentration-independent manner. Concomitant dosing of highly protein-bound drugs is unlikely to affect its disposition.

Metabolism

In both animals and humans, cabergoline is extensively metabolized, predominately via hydrolysis of the acylurea bond or the urea moiety. Cytochrome P-450 mediated metabolism appears to be minimal. Cabergoline does not cause enzyme induction and/or inhibition in the rat. Hydrolysis of the acylurea or urea moiety abolishes the prolactin-lowering effect of cabergoline, and major metabolites identified thus far do not contribute to the therapeutic effect.

Excretion

After oral dosing of radioactive cabergoline to five healthy volunteers, approximately 22% and 60% of the dose was excreted within 20 days in the urine and feces, respectively. Less than 4% of the dose was excreted unchanged in the urine. Nonrenal and renal clearances for cabergoline are about 3.2 L/min and 0.08 L/min, respectively. Urinary excretion in hyperprolactinemic patients was similar.

1. https://www.uptodate.com/contents/Cabergoline -drug-information?search=Cabergoline &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/Cabergoline _2015-1215.pdf
4. https://www.mims.com/india/drug/info/Cabergoline ?type=full&mtype=generic#mechanism-of-action