Kabergolin

Uses

1. Kabergolin is used for the inhibition of physiological lactation soon after delivery, stillbirth, abortion or miscarriage.

2. Kabergolin is used for the treatment of dysfunctions associated with hyperprolactinaemia, including- amenorrhoea, oligomenorrhoea, anovulation and galactorrhoea. Kabergolin is used for patients with prolactin-secreting pituitary adenomas (micro- and macroprolactinomas), idiopathic hyperprolactinaemia, or empty sella syndrome with associated hyperprolactinaemia, which represent the basic underlying pathologies contributing to the above clinical manifestations.

Kabergolin is also used to associated treatment for these conditions: Idiopathic hyperprolactinemic disorder, Inhibition of physiological lactation

How Kabergolin works

The dopamine D₂ receptor is a 7-transmembrane G-protein coupled receptor associated with G_i 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. Kabergolin 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.

Dosage

Kabergolin dosage

Kabergolin is to be administered by the oral route. It should be preferably taken with meals.

The recommended dosage of Kabergolin tablets for initiation of therapy is 0.25 mg twice a week. Dosage may be increased by 0.25 mg twice weekly up to a dosage of 1 mg twice a week according to the patient's serum prolactin level. Dosage increases should not occur more rapidly than every 4 weeks, so that the physician can assess the patient's response to each dosage level. If the patient does not respond adequately and no additional benefit is observed with higher doses, the lowest dose that achieved maximal response should be used and other therapeutic approaches considered. After a normal serum prolactin level has been maintained for 6 months, Kabergolin may be discontinued, with periodic monitoring of the serum prolactin level to determine whether or when treatment with Kabergolin should be reinstituted.

Inhibition of physiological lactation: Kabergolin should be administered during the first day after delivery. The recommended therapeutic dose is 1mg (two 0.5mg tablets) as a single dose.

To stop lactation once have started to breastfeed: 0.25 mg (one half of Kabergolin 0.5 mg tablet) every 12 hours for two days.

Treatment of hyperprolactinaemic disorders: The recommended initial dosage of Kabergolin is 0.5mg per week given in one or two (½ of a 0.5mg tablet) doses (e.g. on Monday and Thursday) per week. The weekly dose should be increased gradually preferably by adding 0.5mg per week at monthly intervals. The therapeutic dosage is usually 1mg per week and ranges from 0.25 to 2mg per week. Doses of Kabergolin up to 4.5mg per week have been used in hyperprolactinaemic patients until the optimal therapeutic response is achieved.

Severe hepatic insufficiency: Lower doses should be considered in patients with severe hepatic insufficiency.

Children: The safety and efficacy of Kabergolin has not been established in subjects less than 16 years of age.

Elderly: Data for use of Kabergolin in elderly is very limited. Available data do not indicate a special risk.

Side Effects

All side effects were mild to moderate in severity and of a transient nature. The most frequently occurring adverse events were dizziness/vertigo, headache, nausea and abdominal pain. In addition rarely palpitations, epigastric pain, somnolence, epistaxis and transient hemianopsia, vomiting, syncope, asthenia, and hot flushes were reported. Kabergolin withdrawal results in reversal of side effects, usually within a few days after discontinuation.

Asymptomatic decreases in blood pressure (20mmHg systolic and 10mmHg diastolic) may occur usually once during the first 3-4 days after child birth.

Toxicity

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

Precaution

Hypersensitive (allergic) to Kabergolin, to other medicines called ergot alkaloids, (e.g. pergolide, bromocriptine, lisuride, ergotamine or ergometrine) or to any of the other ingredients in the tablet.

Severe liver disease and High blood pressure in pregnancy associated with swelling and protein in the urine.

Anti-psychotics or have a history of mental illness associated with child-birth.

Interaction

Kabergolin should not be administered concurrently with –D2 antagonists, such as Phenothiazines, Butyrophenones, Thioxanthenes, Or Metoclopramide.

Medicines to lower blood pressure. Medicines used to treat mental illness (e.g. antipsychotic medicines like chlorpromazine, haloperidol). Medicines for nausea and vomiting (e.g. domperidone). Medicines for severe migraine headaches (e.g. pergolide bromocriptine, lisuride, ergotamine, dihydroergotamine, ergometrine or methysergide).

Food Interaction

• Exercise caution with grapefruit products. Kabergolin is partially metabolized through the CYP3A4 pathway. Therefore coadministration with grapefruit, a CYP3A4 inhibitor, may increase its serum concentration.
• Exercise caution with St. John's Wort. Kabergolin is partially metabolized through the CYP3A4 pathway. Therefore coadministration with St. John's Wort, a CYP3A4 inducer, may reduce its serum concentration.
• Take with or without food. Taking cabergoline with food may reduce gastric irritation.

[Moderate] GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents.

Use in combination may result in additive central nervous system depression and
MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol.

Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Kabergolin Hypertension interaction

[Major] The use of cabergoline is contraindicated in patients with uncontrolled hypertension.

Kabergolin is a dopamine agonist and effects on alpha and

Kabergolin Drug Interaction

Unknown: amphetamine / dextroamphetamine, amphetamine / dextroamphetamine, duloxetine, duloxetine, omega-3 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, escitalopram, escitalopram, levothyroxine, levothyroxine, cyanocobalamin, cyanocobalamin, ascorbic acid, ascorbic acid, ergocalciferol, ergocalciferol, cholecalciferol, cholecalciferol, alprazolam, alprazolam

Kabergolin Disease Interaction

Major: cardiac valvular disorders, hypertension, hypotension, psychosisModerate: hepatic dysfunction

Elimination Route

First-pass effect is seen, however the absolute bioavailability is unknown.

Half Life

The elimination half-life is estimated from urinary data of 12 healthy subjects to range between 63 to 69 hours.

Clearance

• renal cl=0,008 L/min
• nonrenal cl=3.2 L/min

Elimination Route

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.

Pregnancy & Breastfeeding use

Treated with Kabergolin for a long period and have or had fibrotic reactions (scar tissue) affecting your heart.

During pregnancy: Before Kabergolin administration, pregnancy should be excluded. Kabergolin should be used during pregnancy only if clearly needed. If conception occurs during therapy with Kabergolin, discontinuation of treatment should be considered, after careful evaluation of the risks and benefits to mother and foetus.

During lactation: No information is available on the excretion in breast milk in humans; however, mothers should be advised not to breast-feed in case of failed lactation inhibition/suppression by Kabergolin. Since it prevents lactation, Kabergolin should not be administered to mothers with hyperprolactinaemic disorders who wish to breast-feed their infants.

Contraindication

History of serious mental disease, particularly psychotic disorders. Liver or kidney disease n High blood pressure in pregnancy associated with swelling and protein in the urine (toxaemia of pregnancy). Anti-psychotics or have a history of mental illness associated with child-birth (puerperal psychosis).

Acute Overdose

There is no experience in humans of overdosage with Kabergolin in the proposed indications: it is likely to lead to symptoms due to over-stimulation of dopamine receptors.

These might include nausea, vomiting, gastric complaints, hypotension, nasal congestion, confusion hallucinations, psychosis or thought/perception disturbances. Treatment of overdose is symptomatic and supportive.

In addition, in case of pronounced central nervous system effects the administration of dopamine antagonist drugs may be advisable.

Storage Condition

Store in a cool & dry place, protected from light and moisture.

Keep out of reach of children.

Innovators Monograph

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