Professional Information
Cabergoline (Systemic)
VA CLASSIFICATION
Primary: AU900
Secondary: HS900
Commonly used brand name(s): Dostinex.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Dopamine agonist—
antihyperprolactinemic—
Indications
Accepted
Hyperprolactinemic disorders (treatment) or
Prolactinomas, pituitary (treatment)—Cabergoline is indicated in the treatment of hyperprolactinemic disorders due to pituitary adenomas or to idiopathic etiology. {01}
Acceptance not established
There are insufficient data to show that cabergoline is safe and effective for suppression of postpartum lactation.{04} The routine use of medication to suppress postpartum lactation has become controversial and some medical experts now regard this practice as obsolete.{05}
There are insufficient data to show that cabergoline is safe and effective for the treatment of Parkinson's disease.{06}{07}
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Chemical group—
Cabergoline is an ergoline (ergot alkaloid derivative) {01}.
Molecular weight—
451.62 {02}
Mechanism of action/Effect:
Cabergoline is a long-acting, selective dopamine receptor agonist, exhibiting high affinity for D 2 receptors and low affinity for D 1, alpha 1- and alpha 2-adrenergic, and serotonin (5-hydroxytryptamine 1 and 5-hydroxytryptamine 2) receptors. Cabergoline inhibits the synthesis and release of prolactin from the anterior pituitary by directly stimulating the D 2 receptors of the pituitary lactotrophs in a dose-related fashion {01}. While cabergoline doses up to 2 mg inhibited prolactin in healthy volunteers, similar inhibition did not occur for the other anterior pituitary hormones, including growth hormone, follicle-stimulating hormone, luteinizing hormone, corticotropin, and thyroid-stimulating hormone. Cabergoline did not affect serum cortisol concentrations {01}.
Absorption:
Exhibits first-pass effect; absolute bioavailability is unknown {01}.
Distribution:
Extensive tissue distribution; cabergoline concentrations are at least 100 times greater in the pituitary than in the serum. Studies done in rats showed significant concentrations of cabergoline in the mammary glands and uterine wall, and that cabergoline crosses the placenta {01}.
Protein binding:
Moderate (40 to 42%), in a concentration-independent manner. Cabergoline's protein binding is unlikely to be influenced by concomitant treatment with other protein-bound medications. {01}
Biotransformation:
Hepatic—Cabergoline undergoes hydrolysis to inactive metabolites without causing hepatic enzyme induction or inhibition; cytochrome P450–mediated metabolism is minimal {01}. Although mild to moderate hepatic function impairment does not alter pharmacokinetic values for cabergoline, severe hepatic function impairment (Child-Pugh score greater than 10) can substantially increase the values of C max and area under the plasma concentration–time curve (AUC) {01}.
Half-life:
Elimination—63 to 69 hours {01}.
Time to peak concentration:
Within 3 hours {01}.
Peak serum concentration:
30 to 70 picograms/mL (66.4 to 155 picomoles/L), reported in healthy volunteers taking single doses of 0.5 to 1.5 mg cabergoline. The steady-state serum concentration in patients using multiple weekly doses is expected to be 2 to 3 times higher than that reported for single doses. {01}
Time to peak effect:
48 hours (single 0.6-mg dose of cabergoline in hyperprolactinemic patients) {01}.
Duration of action:
Up to 14 days (single 0.6-mg dose of cabergoline in hyperprolactinemic patients) {01}.
Elimination:
At 20 days for five healthy patients given single doses—
• Fecal: 60% {01}.
• Renal: 22% (4% unchanged) {01}.
Nonrenal clearance was 3.2 L per minute in healthy adults. Renal clearance was 0.08 L per minute, similar to that of hyperprolactinemic patients {01}. Moderate-to-severe renal insufficiency did not alter cabergoline's pharmacokinetics {01}.
Precautions to Consider
Cross-sensitivity and/or related problems
Patients sensitive to other ergot derivatives may be sensitive to cabergoline also {01}.
Carcinogenicity/Tumorigenicity
In studies of mice, a slight increase in cervical and uterine leiomyomas and uterine leiomyosarcomas occurred when cabergoline was given in doses seven times the maximum recommended human dose (MRHD)—a dose based on the body surface area (BSA) of a 50-kg human. Cabergoline, when given to rats at doses four times greater than the MRHD, caused a slight increase in interstitial cell adenomas and malignant tumors of the uterus and cervix. {01} The relevance of these findings to humans is not clear because of the hormonal differences between humans and animals {01}.
Mutagenicity
Cabergoline was not found to be mutagenic in a series of in vitro tests {01}, including the Ames test, gene mutation assay, chromosomal aberration test in human lymphocytes, and a DNA damage and repair test in bacteria. Cabergoline also produced a negative mouse bone marrow micronucleus test {01}.
Pregnancy/Reproduction
Fertility—
Cabergoline doses equal to one twenty-eighth of the MRHD inhibited conception in studies of female rats {01}.
Pregnancy—
Adequate and well-controlled studies in humans have not been done. Cabergoline is not recommended for use during pregnancy {01}.
Cabergoline crosses the placenta in animals. Researchers studied cabergoline's effect on reproduction in mice, rats, and rabbits. Maternotoxicity, but not teratogenicity, occurred in studies of mice given doses of cabergoline 55 times greater than the MRHD (based on body surface area of a 50-kg human). When given doses of cabergoline equal to one seventh of the MRHD, rats experienced embryofetal loss after embryo implantation. Similar studies in rabbits given doses 19 times greater than the MRHD produced maternotoxicity, exhibited as reduced food intake and body weight loss. Doses 150 times greater than the MRHD produced fetal malformations in rabbits in one study, a result not reproduced in another study using doses 300 times greater than the MRHD. The relevance of these findings to humans is not clear since prolactin affects the reproductive cycles of animals and humans differently {01}.
FDA Pregnancy Category B {01}.
Breast-feeding
It is not known if cabergoline is distributed into breast milk. Cabergoline should not be used in breast-feeding women or women planning to begin breast-feeding within a short period of time since it inhibits lactation by suppressing prolactin release {01}.
In a study in rats, continued treatment of female rats with cabergoline beginning 6 days before parturition resulted in arrested pup growth and death of the litter due to the decreased amount of available maternal milk {01}.
Pediatrics
Appropriate studies on the relationship of age to the effects of cabergoline have not been performed in the pediatric population. Safety and efficacy have not been established {01}.
Geriatrics
No information is available on the relationship of age to the effects of cabergoline in geriatric patients. Safety and efficacy have not been established {01}.
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Antihypertensives{01} , including
Methyldopa
Reserpine (concurrent use may result in additive hypotensive effects; dosage adjustment of the antihypertensive agent may be needed {01})
» Dopaminergic blocking agents, including metoclopramide{01} or
» Neuroleptics, including
Haloperidol{01}{02}
Phenothiazines{01}{02}
Thioxanthenes{01}{02} (cabergoline may interfere with the dopamine-blocking effects of these medications, reducing their effectiveness and exacerbating the patient's underlying condition; dosage adjustment of either medication may be necessary {01})
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Except under special circumstances, this medication should not be used when the following medical problems exist:
» Eclampsia, or history of or
» Hypertension, uncontrolled or
» Preeclampsia, or history of (may aggravate these conditions; although cabergoline usually lowers blood pressure, rarely, blood pressure can increase {01})
» Hepatic function impairment, severe{01} (metabolism may be reduced with severe hepatic function impairment; dosage reduction may be required if cabergoline is used)
Risk-benefit should be considered when the following medical problems exist
Hepatic function impairment, mild to moderate{01} (although mild to moderate hepatic function impairment does not decrease cabergoline metabolism, special hepatic function and serum prolactin monitoring as a precaution may be warranted; a lower dose of cabergoline may be needed if condition worsens {01})
Sensitivity to cabergoline or other ergot derivatives{01}
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
Blood pressure measurements (initial doses of cabergoline above 1 mg can cause orthostatic hypotension {01}; monitoring for possible hypotensive effects may be needed)
Prolactin, serum (periodic monitoring of serum prolactin concentrations is needed during treatment, after each dosing interval, or when cabergoline is discontinued to assess efficacy of treatment. If serum prolactin levels are normal for 6 months, cabergoline can be discontinued. Patient monitoring should be continued to assess if or when to reinstate the antihyperprolactinemic treatment {01})
Side/Adverse Effects
Note: Side effects for cabergoline are dose-related. Patients using cabergoline for Parkinson's disease, an unlabeled use, receive much higher doses than do those patients with a hyperprolactinemic condition. At doses up to 11.5 mg of cabergoline a day, patients with Parkinson's disease have experienced the following additional side effects: dyskinesia, hallucinations, heart failure, pleural effusion, pulmonary fibrosis, gastric or duodenal ulcer, and, in one case, constrictive pericarditis {01}.
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence less frequent—4 or 5%
Abdominal pain {01}
vertigo (sensation of motion, usually whirling, either of oneself or of one's surroundings){01}
Incidence rare—£ 1%
Anorexia (loss of appetite associated with weight loss or gain){01}
edema, periorbital (vision changes)
edema, peripheral (swelling of hands, ankles, or feet){01}
impaired concentration {01}
syncope or hypotension{01} (fainting or lightheadedness when getting up from a lying or sitting position; unusually fast heartbeat)—especially orthostatic hypotension{01}
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Asthenia (weakness)—incidence 6%{01}
constipation —incidence 7%{01}
dizziness —incidence 17%{01}
dyspepsia (stomach discomfort following meals)—incidence 4%{01}
headache —incidence 26%{01}
nausea —incidence 29%{01}
Incidence less frequent—< 3%
Diarrhea {01}
dryness of mouth {01}
flatulence (stomach or intestinal gas){01}
flu-like symptoms (general feeling of discomfort or illness; runny nose; sore throat){01}
hot flashes {01}
insomnia (trouble in sleeping){01}
mental depression {01}
muscle or joint pain {01}
paresthesia (unusual feeling of burning or stinging of skin){01}
pruritus (itching of skin){01}
somnolence (sleepiness){01}
toothache {01}
vomiting {01}
Those not indicating need for medical attention
Incidence less frequent—< 1%
Acne {01}
increased libido (increased sex drive){01}
Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).
Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Hallucinations {01}
nasal congestion {01}
syncope (fainting; lightheadedness; palpitations){01}
Treatment of overdose
Monitoring—Blood pressure measurements. {01}
Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Cabergoline (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Sensitivity to cabergoline or other ergot derivatives
Carcinogenicity/tumorigenicity
Studies in mice showed slight increase in cervical and uterine leiomyomas and uterine leiomyosarcomas; studies in rats showed a slight increase in malignant tumors of the uterus and cervix and interstitial cell adenomas. Relevancy to humans is not known because prolactin affects animals and humans differently
Pregnancy—Not recommended for use during pregnancy
Breast-feeding—Not known if cabergoline is distributed into breast milk; will prevent lactation in mothers who breast-feed or are planning to begin breast-feeding soon
Other medications, especially dopaminergic blocking agents and neuroleptics
Other medical problems, especially eclampsia (or history of), severe hepatic function impairment, hypertension (uncontrolled), or preeclampsia (or history of)
Proper use of this medication
Compliance with therapy: Importance of not taking more or less medication than the amount prescribed
» Proper dosing
Missed dose: Taking as soon as possible within 1 or 2 days; if missed dose is not remembered until time of next dose, doubling the dose if medication is generally well-tolerated, without causing nausea. If not well-tolerated, discussing with health care professional before taking missed dose
» Proper storage
Precautions while using this medication
Regular visits to physician to check progress
» Caution when driving or doing jobs requiring alertness because of possible drowsiness or dizziness
Checking with physician immediately if pregnancy is suspected
Getting up slowly from sitting or lying position to decrease the incidence of dizziness, lightheadedness, or vertigo
Side/adverse effects
Signs of potential side effects, especially abdominal pain, vertigo, anorexia, periorbital or peripheral edema, impaired concentration, or syncope or hypotension
General Dosing Information
The use of cabergoline for longer than 24 months has not been established {01}. After the patient's serum prolactin level is normal for 6 months, cabergoline may be discontinued. Treatment of hyperprolactinemia may be symptomatic rather than curative; reinitiation of an antihyperprolactinemic agent may be needed {01}.
Oral Dosage Forms
CABERGOLINE TABLETS
Usual adult dose
Antihyperprolactinemic
Oral, 0.25 mg two times a week. In accordance with patient's serum prolactin level, dosage may be increased in increments of 0.25 mg, up to 1 mg two times a week, waiting at least four weeks between each dosage increase {01}.
Usual adult prescribing limits
2 mg a week {02}.
Usual pediatric dose
Antihyperprolactinemic
Safety and efficacy have not been established {01}.
Usual geriatric dose
Antihyperprolactinemic
See Usual adult dose .
Strength(s) usually available
U.S.—
0.5 mg (Rx) [Dostinex (scored) (lactose)]{01}
Packaging and storage:
Store below 40 ºC (104 ºF), preferably between 15 and 30 ºC (59 and 86 ºF), unless otherwise specified by manufacturer. {01}
Developed: 06/26/1997
Revised: 03/05/2001
References
- Dostinex package insert (Pharmacia & Upjohn—US), Rev 12/1996, Rec 2/1997.
- Fleeger CA, editor. USP dictionary of USAN and international drug names 1997. Rockville, MD: The United States Pharmacopeial Convention, Inc.; 1996. p. 119.
- Manufacturer's comment, 4/15/1997.
- Reviewers' responses to Obstetrics and Gynecology Expert Committee Ballot of 11/04/2000.
- Expert committee comment, 11/04/2000.
- Consensus of expert committee on ballot of 10/05/2000, reached 11/30/2000.
- Expert committee comment, 11/24/2000.
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