DOSTINOVA

Cabergoline, an ergot derivative, is a long-acting dopamine agonist and prolactin inhibitor.

It is used to treat hyperprolactinemic disorders and Parkinsonian Syndrome.

Cabergoline possesses potent agonist activity on dopamine D2 receptors.

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 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 D and D 5 subreceptors, which are associated with dyskinesias.

D2 receptor subfamily consists of D 2, D and D 4 subreceptors, which are associated with improvement of symptoms of movement disorders.

Thus, agonist activity specific for D2 subfamily receptors, primarily D and D 3 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 D 2.

• and D 3 -receptors.

It also exhibits: agonist activity (in order of decreasing binding affinities) on 5-hydroxytryptamine (5-HT) 2B, 5-HT 2A, 5-HT 1D, dopamine D 4, 5-HT 1A, dopamine D 1, 5-HT 1B and 5-HT 2C receptors and antagonist activity on α 2B, α 2A, and α 2C receptors.

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.

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

Cabergoline is extensively metabolized, predominately via hydrolysis of the acylurea bond of the urea moiety.

P-450 mediated metabolism appears to be minimal.

The main metabolite identified in urine is 6-allyl-8b-carboxy-ergoline (4-6% of dose).

Three other metabolites were identified urine (less than 3% of dose).

Hover over products below to view reaction partners Cabergoline 6-allyl-8b-carboxy-ergoline.

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.

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

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

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

Dopamine agonists in general should not be used in patients with pregnancy-induced hypertension, for example, preeclampsia, eclampsia, and postpartum hypertension, unless the potential benefit is judged to outweigh the possible risk. 2.

All patients should undergo a cardiovascular evaluation, including echocardiogram to assess the potential presence of valvular disease.

If valvular disease is detected, the patient should not be treated with Cabergoline See CONTRAINDICATIONS .

Post-marketing cases of cardiac valvulopathy have been reported in patients receiving Cabergoline.

These cases have generally occurred during administration of high doses of Cabergoline (>2mg/day) used for the treatment of Parkinson’s disease.

Cases of cardiac valvulopathy have also been reported in patients receiving lower doses for the treatment of hyperprolactinemic disorders.

A multi-country, retrospective cohort study using general practice records and record linkage systems in the UK, Italy and the Netherlands was conducted to assess the association between new use of dopamine agonists including cabergoline (n=27,812) for Parkinson’s disease and hyperprolactinemia and cardiac valvular regurgitation (CVR), other fibroses, and other cardiopulmonary events over a maximum of 12 years of follow up.

In this study, the use of cabergoline among persons with Parkinson’s disease was associated with an increased risk of CVR when compared to non-ergot-derived dopamine agonists (Das) and levodopa [Incidence Rate (IR) per 10,000 person years of 68.1 (95% confidence interval (CI): 37.2 to 115.3) for cabergoline vs. 10.0 (95% CI: 5.2 to 19.4) for non-ergot Das and 11.3 (95% CI: 7.2 to 17.0) for levodopa.

In the study analysis confined to persons with dopamine agonist-treated hyperprolactinemia (n=8,386), when compared to non-use (n=15,147), persons exposed to cabergoline did not have an elevated risk of CVR.

The findings with respect to the risk of CVR associated with cabergoline treatment for persons with Parkinson’s disease (increased risk) and those with hyperprolactinemia (no increased risk) are consistent with the findings in other published studies.

Physicians should use the lowest effective dose of Cabergoline for the treatment of hyperprolactinemic disorders and should periodically reassess the need for continuing therapy with Cabergoline.

Following treatment initiation, clinical and diagnostic monitoring (for example, chest x-ray, CT scan and cardiac echocardiogram) should be conducted to assess the risk of cardiac valvulopathy.

The recommended frequency of routine echocardiographic monitoring is every to 12 months or as clinically indicated with the presence of signs and symptoms such as edema, new cardiac murmer, dyspnea or congestive heart failure.

Cabergoline should be discontinued if an echocardiogram reveals new valvular regurgitation, valvular restriction or valve leaflet thickening.

Cabergoline should be used with caution in patients exposed to other medications associated with valvulopathy. b.

Post-marketing cases of pleural, pericardial and retroperitoneal fibrosis have been following administration of Cabergoline.

Some reports were in patients previously treated with other ergotinic dopamine agonists.

Cabergoline should not be used in patients with a history of cardiac or extracardiac fibrotic disorders.

Fibrotic disorders can have an insidious onset and patients should be monitored for manifestations of progressive fibrosis.

Therefore, during treatment, attention should be paid to the signs and symptoms of: Pleuro-pulmonary disease such as dyspnea, shortness of breath, persistent cough or chest pain.

Renal insufficiency or ureteral/abdominal vascular obstruction that may occur with pain in the loin/flank and lower limb edema as well as any possible abdominal masses or tenderness that may indicate retroperitoneal fibrosis.

Cardiac failure

Cases of valvular and pericardial fibrosis have ofter manifested as cardiac failure.

Therefore, valvular fibrosis (and constrictive pericarditis) should be excluded if such symptoms occur.

Clinical and diagnostic monitoring such as erythrocyte sedimentation rate, chest x-ray, serum creatinine measurements, and other investigations should be considered at baseline and as necessary while patients are treated with Cabergoline.

Following diagnosis of pleural effusion or pulmonary fibrosis, the discontinuance of Cabergoline was reported to result in improvement of signs and symptoms.

Tablets, USP are contraindicated in patients with Uncontrolled hypertension or known hypersensitivity to ergot derivatives.

History of cardiac valvular disorders, as suggested by anatomical evidence of valvulopathy of any valve, determined by pre-treatment evaluation including echocardiographic demonstration of valve leaflet thickening, valve restriction, or mixed valve restriction-stenosis See WARNINGS.

History of pulmonary, pericardial, or retroperitoneal fibrotic disorders See WARNINGS.

The recommended dosage of Cabergoline

Tablets, USP 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.

Before initiating treatment, cardiovascular evaluation should be performed and echocardiography should be considered to assess for valvular disease.

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.

Patients receiving long term treatment with

Cabergoline should undergo periodic assessment of their cardiac status and echocardiography should be considered.

After a normal serum prolactin level has been maintained for 6 months, cabergoline may be discontinued, with periodic monitoring of the serum prolactin level to determine whether or when treatment with cabergoline should be reinstituted.

The durability of efficacy beyond 24 months of therapy with cabergoline has not been established.

Tablets, USP are a white to off-white, oval shape, flat face, beveled edge tablet containing 0.5 mg cabergoline USP.

Each tablet is debossed “P” bisect line “P” on one side and “673" on the other side.

Tablets, USP are available as follows: Bottles of 8 tablets NDC 70512-860-08.

Store at controlled room temperature 20° to 25° C (68° to 77° F) .

Dispense in original container.

Distributed by

SOLA Pharmaceuticals Baton Rouge, LA 70810.

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/m 2 /week for animals and mg/m 2 /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 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.

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.

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.

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

Clinical studies of cabergoline did not include sufficient numbers of subjects aged 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.