Cabergoline

Pronunciation

Class: Ergot-derivative Dopamine Receptor Agonists
VA Class: AU900
Chemical Name: 1-[(6-allylergolin-8β-yl)-carbonyl]-1-[3-(dimethylamino)propyl]-3-ethylurea
Molecular Formula: C26H37N5O2
CAS Number: 81409-90-7
Brands: Dostinex

Introduction

An ergot-derivative dopamine receptor agonist and prolactin inhibitor.1 2 3 8 10 11 12 15

Uses for Cabergoline

Hyperprolactinemic Disorders

Treatment of hyperprolactinemic disorders due to prolactinoma (prolactin-secreting adenomas) or idiopathic hyperprolactinemia.1 2 3 12 13 14 Suppresses prolactin secretion, restores gonadal function, and reduces the size of prolactinomas.1 2 3 12 13 14

At least as effective as bromocriptine in normalizing serum prolactin concentrations and restoring gonadal function in women with hyperprolactinemic amenorrhea.12 13 Fewer adverse effects, especially adverse GI effects, reported in cabergoline-treated women than in bromocriptine-treated women.12 13 14 Bromocriptine preferred when restoration of fertility is the goal of therapy; this recommendation is based on the safety record of bromocriptine in pregnant women.14

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Parkinsonian Syndrome

Has been used for the symptomatic management of parkinsonian syndrome.4 5 6 7 8 9 10 11

Has been used as monotherapy for initial symptomatic management of parkinsonian syndrome.8 9 11 Most clinicians would use levodopa for initial therapy in individuals >70 years of age (less likely than younger individuals to develop levodopa-related motor complications and because of concerns about cognitive dysfunction), in patients with cognitive impairment, and in those with severe disease.7 A dopamine receptor agonist may be preferred for initial therapy in patients ≤70 years of age.7

Has been used as an adjunct to levodopa for the symptomatic management of parkinsonian syndrome in patients with advanced disease.4 5 6 8 10

Cabergoline Dosage and Administration

Administration

Oral Administration

Administer orally without regard to meals.1

Hyperprolactinemic disorders: Administer twice weekly.1

Parkinsonian syndrome: Administer once daily.8

Dosage

Adults

Hyperprolactinemic Disorders
Oral

Initiate at low dosage and increase slowly (at ≥4 week intervals) until therapeutic response is achieved.1

Initially, 0.25 mg twice weekly; increase in increments of 0.25 mg twice weekly up to 1 mg twice weekly.1 Base dosage adjustments on serum prolactin concentrations; use lowest effective dosage.1

Consider decreasing the dosage if normal serum prolactin concentrations maintained for 24 months and size of tumor decreased ≥50%; periodically monitor to determine whether retreatment is needed.14 15 Some patients (e.g., those with microadenomas) may be able to discontinue the drug; discontinuance in those with macroadenomas should be undertaken with extreme caution.14 15 The manufacturer states that efficacy >24 months not established.1

Parkinsonian Syndrome
Oral

Initiate at low dosage and increase slowly (at intervals of 7 or 14 days) until the maximum therapeutic response is achieved.8

2–6 mg daily has been used.8

Therapy has been initiated with 1 mg once daily, then increased in increments of 0.5–1 mg at 7 or 14 day intervals until control of symptoms obtained.8

When cabergoline is used as an adjunct to levodopa, the levodopa dosage may be decreased gradually as tolerated.8

When therapy with a dopamine receptor agonist is discontinued, the drug is discontinued gradually.18

Prescribing Limits

Adults

Hyperprolactinemic Disorders
Oral

Dosages >1 mg twice weekly have not been systematically evaluated.1

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time; use with caution in patients with severe hepatic impairment.1 (See Hepatic Impairment under Cautions and also see Absorption: Special Populations, under Pharmacokinetics.)

Renal Impairment

No specific dosage recommendations at this time.1 (See Elimination: Special Populations, under Pharmacokinetics.)

Geriatric Patients

Select dosage carefully; start at low dosage.1 (See Geriatric Use under Cautions.)

Cautions for Cabergoline

Contraindications

  • Known hypersensitivity to cabergoline or other ergot derivatives.1

  • Uncontrolled hypertension.1

Warnings/Precautions

Warnings

Hypertension during Pregnancy

Should not be used in patients with pregnancy-induced hypertension (e.g., preeclampsia, eclampsia) unless potential benefits outweigh possible risks.1

Fibrotic Effects

Pleural effusion, pulmonary fibrosis, and cardiac valvulopathy reported.1 16 Signs and symptoms have improved after discontinuance.1

Use with caution in patients with history of, or current signs and/or symptoms of, respiratory or cardiac disorders linked to fibrotic tissue.1

General Precautions

When used for parkinsonian syndrome, observe the usual precautions associated with dopamine receptor agonist therapy in this patient population.8 9 17 18 Usual dosage for parkinsonian syndrome exceeds dosage used for hyperprolactinemia.1 17

Symptomatic Hypotension

Orthostatic hypotension reported, especially if initial doses >1 mg are used.1 Exercise care in patients currently receiving drugs known to lower BP.1

Postpartum Breast Engorgement

Not indicated for the inhibition or suppression of lactation.1 Hypertension, cerebrovascular accidents, and seizures reported rarely when another dopamine receptor agonist (i.e., bromocriptine) was used for this indication.1

Specific Populations

Pregnancy

Category B.1 (See Hypertension during Pregnancy under Cautions.)

Lactation

Not known whether cabergoline is distributed into milk; drug is expected to interfere with lactation.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

Insufficient experience from clinical studies to determine whether patients ≥65 years of age respond differently than younger adults.1 Other clinical experience has not identified age-related differences in responses.1

Select dosage carefully, generally initiating therapy at low dosage.1 Consider the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy in geriatric patients.1 2 3

Hepatic Impairment

Cabergoline extensively metabolized in liver; use with caution and monitor carefully.1 (See Absorption: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Patients with hyperprolactinemia: Nausea, constipation, abdominal pain, headache, dizziness, asthenia, fatigue, somnolence.1

Patients with parkinsonian syndrome: Dyskinesia, hallucinations, confusion, peripheral edema.1

Interactions for Cabergoline

Specific Drugs

Drug

Interaction

Comments

Dopamine antagonists (e.g., phenothiazines, butyrophenones, thioxanthenes, metoclopramide)

Possible reduced efficacy of cabergoline1

Generally should not be used concomitantly1 8

Levodopa

Additive therapeutic and/or adverse (e.g., dyskinesia) effects8

Consider a reduction in levodopa dosage when cabergoline is added to levodopa therapy8

Cabergoline Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations usually attained within 1–2 hours.1 17

Absolute bioavailability unknown.1 17

Onset

Following oral administration of a single 0.6-mg dose of cabergoline, time to maximum prolactin-lowering effect was 48 hours.1

Duration

Prolactin-lowering effect persists for 14 days.1

Food

Food does not alter the pharmacokinetics of cabergoline.1

Special Populations

Peak plasma concentrations and AUC not altered in patients with mild to moderate hepatic impairment (Child Pugh score ≤10).1 Peak plasma concentrations and AUC substantially increased in patients with severe impairment (Child Pugh score >10).1

Distribution

Extent

Extensively distributed throughout the body, including the CNS.1 8

Plasma Protein Binding

40–42%.1 17

Elimination

Metabolism

Metabolized in the liver (minimal CYP involvement), mainly by hydrolysis of the acylurea bond;1 17 undergoes substantial first-pass metabolism.1

Elimination Route

Excreted in feces (72%) and in urine (18% as metabolites and unchanged drug).17

Half-life

63–109 hours.1 17

Special Populations

Pharmacokinetic values not altered in patients with moderate to severe renal impairment.1 17

Stability

Storage

Oral

Tablets

20–25°C.1

Actions

  • A long-acting dopamine receptor agonist; has high binding affinity for dopamine D2 receptors and lesser affinity for D1, α1- and α2-adrenergic, and serotonin (5-HT1 and 5-HT2) receptors.1 8

  • Reduces serum prolactin concentrations by inhibiting release of prolactin from the anterior pituitary gland.1 This effect on hypothalamic/pituitary function attributed to the drug’s agonist activity at D2 receptors.1

Advice to Patients

  • Potential for hypotension.1

  • Importance of patients informing clinicians if cough or dyspnea develop.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., respiratory or cardiac disorders associated with fibrosis).1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Cabergoline

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

0.5 mg

Dostinex (scored)

Pfizer

Cabergoline

Teva, Par

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Pfizer Inc. Dostinex(cabergoline) tablets prescribing information. New York, NY; 2007 Feb.

2. Webster J, Piscitelli G, Polli A et al. Dose-dependent suppression of serum prolactin by carbergoline in hyperprolactinemia: a placebo controlled, double blind, multicentre study. Clin Endocrinol. 1992; 37:534-41.

3. Webster J, Piscitelli G, Polli A et al. The efficacy and tolerability of long-term cabergoline therapy in hyperprolactinemic disorders; an open, uncontrolled, multicentre study. Clin Endocrinol. 1993; 39:323-9.

4. Clarke CE, Deane KHO. Cabergoline versus bromocriptine for levodopa-induced complications in Parkinson’s disease. Cochrane Database of Systematic Reviews 2001, Issue 1. Art. No.: CD001519. DOI: 10.1002/14651858.CD001519.

5. Clarke CE, Deane KHO. Cabergoline for levodopa-induced complications in Parkinson’s disease. Cochrane Database of Systematic Reviews 2001, Issue 1. Art. No.: CD001518. DOI: 10.1002/14651858.CD001518.

6. Pahwa R, Factor SA, Lyons KE et al. Practice parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): Report of the quality standards subcommittee of the American Academy of Neurology. Neurology. 2006; 66:983-95. [PubMed 16606909]

7. Olanow CW, Watts, RL, Koller WC. An algorithm (decision tree) for the management of Parkinson’s disease: treatment guidelines (2001). Neurology. 2001; 56 (Suppl):S1-88. [PubMed 11402154]

8. Curran MP, Perry CM. Cabergoline: a review of its use in the treatment of Parkinson’s disease. Drugs. 2004; 64:2125-41. [PubMed 15341508]

9. Miyasaki JM, Martin W, Suchowersky O et al. Practice parameter: initiation of treatment for Parkinson’s disease: an evidence-based review: Report of the quality standards subcommittee of the American Academy of Neurology. Neurology. 2002; 58:11-7. [PubMed 11781398]

10. Marsden CD. Clinical experience with cabergoline in patients with advanced Parkinson’s disease treated with levodopa. Drugs. 1998; 55 (Suppl 1):17-22. [PubMed 9483166]

11. Rinne UK, Bracco F, Chouza C et al. Early treatment of Parkinson’s disease with cabergoline delays the onset of motor complications: results of a double-blind levodopa controlled trial: The PKDS009 Study Group. Drugs. 1998; 55 (Suppl 1):23-30. [PubMed 9483167]

12. Webster J, Piscitelli G, Polli A et al. A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea: carbergoline comparative study group. N Engl J Med. 1994; 331:904-9. [PubMed 7915824]

13. Webster J. Dopamine agonist therapy in hyperprolactinemia. J Reprod Med. 1999; 44:1105-10. [PubMed 10649819]

14. Schlechte JA. Prolactinoma. N Engl J Med. 2003; 349:2035-41. [PubMed 14627789]

15. Colao A, Di Sarno A, Cappabianca P et al. Withdrawl of long-term cabergoline therapy for tumoral and nontumoral hyperprolactinemia. N Engl J Med. 2003; 349:2023-33. [PubMed 14627787]

16. Ling LH, Ahlskog JE, Munger TM et al. Constrictive pericarditis and pleuropulmonary disease linked to ergot dopamine agonist therapy (cabergoline) for Parkinson’s disease. Mayo Clin Proc. 1999; 74:371-5. [PubMed 10221467]

17. Del Dotto P, Bonuccelli U. Clinical pharmacokinetics of cabergoline. Clin Pharmacokinet. 2003; 42:633-45. [PubMed 12844325]

18. Valeant Pharmaceuticals. Permax (pergolide mesylate) tablets prescribing information. Costa Mesa, CA; 2003 Nov 11.

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