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CABERGOLINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Cabergoline is an ergoline derivative and a selective dopamine agonist with a high affinity for the D2 receptor site.

Specific Substances

    1) 1-(6-Allylergolin-8beta-yl)carbonyl)-1-(3-(dimethylamino)propyl)-3-ethylurea
    2) (8R)-6-allyl-N-(3-dimethylamino)propyl)-N-(ethylcarbamoyl)ergoline-8-carboxamide
    3) Cabergolin
    4) Cabergolina
    5) Cabergolinum
    6) FCE-21336
    7) CAS 81409-90-7
    1.2.1) MOLECULAR FORMULA
    1) C26-H37-N5-O2

Available Forms Sources

    A) FORMS
    1) Cabergoline is available as 0.5 mg capsule-shaped tablets (Prod Info DOSTINEX(R) oral tablets, 2014).
    B) USES
    1) Cabergoline is indicated for treatment of hyperprolactinemic disorders, either idiopathic or associated with pituitary adenomas(Prod Info DOSTINEX(R) oral tablets, 2014). It has also been used in the treatment for motor complications associated with chronic levodopa therapy for the treatment of Parkinson's disease (Lera et al, 1993; Lera et al, 1990) and for its long-lasting lowering of serum growth hormone and prolactin levels in acromegalic patients (Ferrari et al, 1988).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Cabergoline is indicated for the treatment of hyperprolactinemic disorders, either idiopathic or associated with pituitary adenomas. It has also been used to treat motor complications associated with chronic levodopa therapy for the treatment of Parkinson's disease, and for its long-lasting lowering of serum growth hormone and prolactin levels in acromegalic patients.
    B) PHARMACOLOGY: Cabergoline is a long-acting dopaminergic agonist with a high affinity for D2 receptors. In receptor-binding studies, cabergoline has been shown to have low affinity for dopamine D1, alpha-1 and alpha-2 adrenergic, and 5-HT1- and 5-HT2-serotonin receptors.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Headache, dizziness, postural hypotension, dyskinesias, fatigue, nausea, vomiting, abdominal pain, and constipation may frequently occur with therapeutic administration.
    2) INFREQUENT: Other effects that may occur less frequently include hallucinations, nasal congestion, and elevations of serum transaminases and bilirubin.
    3) RARE: Slight decreases in hemoglobin levels, mild leukopenia and thrombocytopenia have rarely been reported.
    4) CHRONIC: Congestive heart failure and pulmonary fibrosis have been reported with long-term therapy with cabergoline.
    E) WITH POISONING/EXPOSURE
    1) Overdose information is limited. Cabergoline overdose may result in hypotension, nasal congestion, syncope, or hallucinations.
    0.2.20) REPRODUCTIVE
    A) Cabergoline is classified as FDA pregnancy category B. Human reproductive studies of cabergoline have demonstrated congenital anomalies, abortions, low birth weights, premature births and stillbirths. Animal reproductive studies of cabergoline have shown various malformations, post-implantation embryofetal losses, and maternotoxicity. Although cabergoline has not been studied in human lactation, rat studies have demonstrated inhibited growth and death of offspring due to decreased milk secretion. In fertility studies of female rats, inhibited conception was observed when cabergoline was given prior to and throughout the mating period.

Laboratory Monitoring

    A) Monitor blood pressure in symptomatic patients.
    B) Monitor for signs of dyskinesias.
    C) Monitor serum electrolytes in patients with significant vomiting.
    D) Obtain a chest x-ray in symptomatic patients.
    E) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Orthostatic hypotension is frequently reported with cabergoline therapy and may occur following initial doses greater than 1 mg. Patients with mild orthostatic hypotension can be treated by remaining prone. Those who remain hypotensive can be treated with IV fluids. Correct any significant fluid and/or electrolyte abnormalities in patients with severe vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine, if unresponsive to fluids.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain their airway.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain their airway.
    D) AIRWAY MANAGEMENT
    1) Airway management is very unlikely to be necessary unless other toxic agents have been administered concurrently.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION PROCEDURE
    1) It is unknown if hemodialysis would be effective in overdose.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) When managing a suspected cabergoline overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose may be similar to reported side effects of the medication.
    I) PHARMACOKINETICS
    1) Approximately 40% bound to plasma proteins, with extensive tissue distribution. Extensively metabolized in the liver, predominately via hydrolysis of the acylurea bond or the urea moiety. Elimination half-life ranges from 63 to 69 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Included other agents that may cause orthostatic hypotension (eg, guanfacine, vasodilators).

Range Of Toxicity

    A) TOXICITY: A specific minimum toxic dose of cabergoline has not been established.
    B) THERAPEUTIC DOSE: ADULT: For hyperprolactinemic disorders, the recommended initial dose is 0.25 mg orally twice weekly. Based on the patient's serum prolactin level, the dose may be increased in increments of 0.25 mg twice weekly every 4 weeks, up to a MAX dose of 1 mg orally twice weekly. PEDIATRIC: Safety and efficacy have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Cabergoline is indicated for the treatment of hyperprolactinemic disorders, either idiopathic or associated with pituitary adenomas. It has also been used to treat motor complications associated with chronic levodopa therapy for the treatment of Parkinson's disease, and for its long-lasting lowering of serum growth hormone and prolactin levels in acromegalic patients.
    B) PHARMACOLOGY: Cabergoline is a long-acting dopaminergic agonist with a high affinity for D2 receptors. In receptor-binding studies, cabergoline has been shown to have low affinity for dopamine D1, alpha-1 and alpha-2 adrenergic, and 5-HT1- and 5-HT2-serotonin receptors.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Headache, dizziness, postural hypotension, dyskinesias, fatigue, nausea, vomiting, abdominal pain, and constipation may frequently occur with therapeutic administration.
    2) INFREQUENT: Other effects that may occur less frequently include hallucinations, nasal congestion, and elevations of serum transaminases and bilirubin.
    3) RARE: Slight decreases in hemoglobin levels, mild leukopenia and thrombocytopenia have rarely been reported.
    4) CHRONIC: Congestive heart failure and pulmonary fibrosis have been reported with long-term therapy with cabergoline.
    E) WITH POISONING/EXPOSURE
    1) Overdose information is limited. Cabergoline overdose may result in hypotension, nasal congestion, syncope, or hallucinations.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Abnormal visual contrast sensitivity was observed in a randomized, placebo-controlled study of cabergoline in 22 patients. Compared to placebo, mean contrast sensitivity scores of the three highest spatial frequencies (6, 9, and 12 cycles per degree of visual angle) decreased significantly in cabergoline treated patients (Hutton et al, 1996).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) Nasal congestion has been reported following therapeutic administration of cabergoline (Ferrari et al, 1986).
    B) WITH POISONING/EXPOSURE
    1) Nasal congestion may occur as an overdose effect (Prod Info DOSTINEX(R) oral tablets, 2014).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) LOW BLOOD PRESSURE
    1) WITH THERAPEUTIC USE
    a) Slight to moderate reductions in blood pressure have occurred during cabergoline therapy of hyperprolactinemia (Prod Info DOSTINEX(R) oral tablets, 2014; Ferrari et al, 1986; Webster et al, 1993; Ciccarelli et al, 1989; Ferrari et al, 1989; Mattei et al, 1988). After a single dose of 0.3 mg, blood pressure was decreased maximally at 6 hours (10% systolic, 7% diastolic) and tended to normalize within 48 to 72 hours (Ferrari et al, 1986).
    b) INCIDENCE: The incidence of significant orthostatic hypotension has ranged from 1% to 10% in hyperprolactinemic patients, and usually occurs during initiation of therapy, subsiding with dose reduction or continued use in many patients (Ferrari et al, 1992a; Ciccarelli et al, 1989; Ferrari et al, 1989; Mattei et al, 1988); however, its occurrence has occasionally prompted withdrawal of therapy (Ciccarelli et al, 1989).
    c) Orthostatic hypotension (decrease in systolic pressure 20 mmHg or more) was reported in 7% of 136 women receiving a single dose of oral cabergoline 1 mg for lactation inhibition in a large controlled study (Anon, 1991).
    d) Hypotension induced by cabergoline has also been reported in parkinsonian patients treated with daily doses of the drug, usually during the first few days of therapy. Hypotensive effects lessened with continued treatment. Withdrawal of cabergoline due to symptomatic hypotension was required in 1 of 22 patients (Inzelberg et al, 1996; Jori et al, 1990).
    2) WITH POISONING/EXPOSURE
    a) Initial doses greater than 1 milligram may lead to orthostatic hypotension (Prod Info DOSTINEX(R) oral tablets, 2014).
    B) CONGESTIVE HEART FAILURE
    1) WITH THERAPEUTIC USE
    a) Heart failure was reported in one patient with Parkinson's disease following several months of therapy with combined cabergoline and levodopa (Lera et al, 1990). However, a direct association with cabergoline is speculative.
    b) CASE REPORT: Signs and symptoms of congestive heart failure developed in a 76-year-old man receiving cabergoline 10 mg/day for over a year. Echocardiography revealed constrictive pericarditis. After later findings of pleuropulmonary fibrosis, a recognized side effect of other ergoline drugs, the development of constrictive pericarditis was postulated to be associated with the patient's cabergoline therapy. The patient died approximately 2 years later due to progressive, severe dyspnea (Ling et al, 1999).
    C) SYNCOPE
    1) WITH POISONING/EXPOSURE
    a) Syncope may occur following a cabergoline overdose (Prod Info DOSTINEX(R) oral tablets, 2014).
    D) EDEMA
    1) WITH THERAPEUTIC USE
    a) Severe, bilateral lower extremity edema led to drug withdrawal in one patient receiving adjunctive cabergoline 3 milligrams daily for 3 months for Parkinson's disease. Two other patients experiencing lower limb edema continued on treatment (Geminiani et al, 1996). An overall 1% incidence is reported during a comparative trial with bromocriptine (Prod Info DOSTINEX(R) oral tablets, 2014).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) FIBROSIS OF LUNG
    1) WITH THERAPEUTIC USE
    a) Pleuropulmonary changes have been reported in parkinsonian patients following therapy with cabergoline (Geminiani et al, 1996; Frans et al, 1992; Bhatt et al, 1991). Radiological evidence of pleural effusion, pleural thickening, and atelectasis with fibrosis were described in patients following 11 to 16 months of cabergoline therapy; withdrawal of the drug resulted in clinical and radiological improvement after several months.
    b) CASE REPORT: Signs and symptoms of congestive heart failure developed in a 76-year-old man receiving cabergoline 10 mg/day for over a year. Echocardiography revealed constrictive pericarditis. After later findings of pleuropulmonary fibrosis, a recognized side effect of other ergoline drugs, the development of constrictive pericarditis was postulated to be associated with the patient's cabergoline therapy. The patient died approximately 2 years later due to progressive, severe dyspnea (Ling et al, 1999).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has occurred frequently with oral cabergoline therapy in hyperprolactinemic patients (Prod Info DOSTINEX(R) oral tablets, 2014; Anon, 1997; Ferrari et al, 1992a; Webster et al, 1992; Ferrari et al, 1989; Ferrari et al, 1986) and has occasionally required withdrawal of therapy (Ciccarelli et al, 1989).
    1) INCIDENCE
    a) In the largest studies to date, headache has occurred in 9% to 30% of hyperprolactinemic patients receiving cabergoline in weekly doses of 0.2 to 3.5 mg, usually administered once or twice weekly (Webster et al, 1993; Webster et al, 1992; Ferrari et al, 1992a). Headache was not dose-related in one study, and tended to occur early in therapy and subside with continued administration (Ferrari et al, 1992a; Webster et al, 1992).
    b) In women receiving single doses of cabergoline for puerperal lactation inhibition, headache occurred less frequently, with an incidence of less than 10% (Caballero-Gordo et al, 1991; Anon, 1991).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness is a frequent occurrence following cabergoline therapy in hyperprolactinemic patients (Prod Info DOSTINEX(R) oral tablets, 2014; Anon, 1997; Ferrari et al, 1992a; Webster et al, 1992; Ferrari et al, 1986) and has occasionally required withdrawal of therapy (Webster et al, 1992; Ciccarelli et al, 1989).
    b) In the largest studies to date, the incidence of dizziness was 9% to 17% (Webster et al, 1992; Ferrari et al, 1992a). Dizziness was not dose-related in one study, and tended to occur early in therapy and subside with continued administration.
    c) In women receiving single doses of cabergoline for puerperal lactation inhibition, dizziness occurred less frequently, with an incidence of less than 10% (Caballero-Gordo et al, 1991; Anon, 1991). Dizziness tended to be less frequent with cabergoline compared to conventional doses of bromocriptine in one trial. These symptoms are usually observed during the first 24 to 72 hours after administration and subside thereafter (Anon, 1991).
    C) DROWSINESS
    1) WITH THERAPEUTIC USE
    a) Weakness, fatigue, and drowsiness may occur with cabergoline therapy (Webster et al, 1992; Ferrari et al, 1992a; Anon, 1991; Ciccarelli et al, 1989; Ferrari et al, 1989), and have occasionally required discontinuation of treatment. The most common of these effects is fatigue, occurring in 10% of hyperprolactinemic patients in one study (Webster et al, 1992).
    D) DYSKINESIA
    1) WITH THERAPEUTIC USE
    a) Dyskinesias may frequently occur with cabergoline therapy, particularly in patients with Parkinson's disease (Prod Info DOSTINEX(R) oral tablets, 2014; Inzelberg et al, 1996).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting have been frequently reported following therapeutic administration of cabergoline (Ferrari et al, 1992a; Lera et al, 1990; Jori et al, 1990). Nausea appears to be dose-related (Prod Info DOSTINEX(R) oral tablets, 2014; Webster et al, 1992) and has occasionally required withdrawal of therapy (Ciccarelli et al, 1989).
    b) INCIDENCE: Nausea was reported in 27% of patients on cabergoline therapy (n=168) as compared with 20% of patients taking placebo (n=20) (Prod Info DOSTINEX(R) oral tablets, 2014). In one trial (n=168), nausea occurred in 16%, 24%, 33%, and 34% of hyperprolactinemic patients treated with doses of 0.125, 0.5, 0.75, and 1 mg twice weekly, respectively (Webster et al, 1992).
    B) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation is a common adverse effect (Prod Info DOSTINEX(R) oral tablets, 2014; Ferrari et al, 1992a; Webster et al, 1992; Mattei et al, 1988).
    b) INCIDENCE: In one trial (n=168), constipation was observed in 5%, 5%, 19%, and 10% of hyperprolactinemic patients treated with doses of 0.125, 0.5, 0.75, and 1 mg twice weekly, respectively (Webster et al, 1992).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain may occur with cabergoline therapy (Prod Info DOSTINEX(R) oral tablets, 2014; Webster et al, 1992).
    b) INCIDENCE: In one trial (n=168), hyperprolactinemic patients were treated with cabergoline doses of 0.125 mg, 0.5 mg, 0.75 mg, or 1 mg twice weekly; abdominal pain was reported in approximately 7% of patients regardless of dose (Webster et al, 1992).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Elevations of serum transaminases and bilirubin have been reported in some patients treated with oral cabergoline (Webster et al, 1992). However, it is unclear if these changes are drug-related.

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Slight decreases in hemoglobin levels have been reported during cabergoline therapy in one large study (n=188) involving hyperprolactinemic patients, with withdrawal of therapy required in one patient. A definite cause-effect relationship was not established (Webster et al, 1992).
    B) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Single reports of mild leucopenia and thrombocytopenia occurred following therapeutic use of cabergoline (Webster et al, 1992).

Reproductive

    3.20.1) SUMMARY
    A) Cabergoline is classified as FDA pregnancy category B. Human reproductive studies of cabergoline have demonstrated congenital anomalies, abortions, low birth weights, premature births and stillbirths. Animal reproductive studies of cabergoline have shown various malformations, post-implantation embryofetal losses, and maternotoxicity. Although cabergoline has not been studied in human lactation, rat studies have demonstrated inhibited growth and death of offspring due to decreased milk secretion. In fertility studies of female rats, inhibited conception was observed when cabergoline was given prior to and throughout the mating period.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) In a 12-year, prospective, observational study, pregnancy outcomes were analyzed among women who were treated with cabergoline at the time of conception and/or during pregnancy (n=380). In 23 (9%) of the 250 live deliveries, neonatal abnormalities were reported. Neonatal abnormalities included cleft palate, hip dysplasia, cheilognathouranoschisis, click left hip, dolichocephaly, labiognathopalatoschisis, moderate shoulder dystocia, sickle foot, umbilical and left inguinal hernia, persistent foramen ovale and epicatnthus, respiratory failure, gastric hemorrhage, mongolian spot on buttocks, and mild chordee of penis. There was no apparent pattern to the abnormalities (Colao et al, 2008).
    2) In a study of cabergoline-associated pregnancies (n=199), 10 congenital anomalies were reported, with no apparent pattern to the abnormalities (Rains et al, 1995).
    B) LACK OF EFFECT
    1) One report described 56 women treated with cabergoline for amenorrhea secondary to hyperprolactinemia, resulting in 17 pregnancies. Of these 17, there was one spontaneous abortion, 10 normal deliveries at term and 6 outcomes pending. The ten infants delivered without incident have had normal physical and mental development (Ferrari et al, 1992).
    C) ANIMAL STUDIES
    1) RABBITS: An increase in various malformations was reported when rabbits were given cabergoline doses of 4 mg/kg/day (approximately 150 times the maximum human recommended dose) during the period of organogenesis (Prod Info DOSTINEX(R) oral tablets, 2014).
    2) LACK OF EFFECT: In a rabbit study, no malformations or embryofetotoxicity were reported at doses up to 8 mg/kg/day (approximately 300 times the maximum human recommended dose (MRHD)). In a study of mice given cabergoline at doses up to 8 mg/kg/day (approximately 55 times the MRHD) during the period of organogenesis, no teratogenic effects were observed (Prod Info DOSTINEX(R) oral tablets, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified cabergoline as FDA pregnancy category B (Prod Info DOSTINEX(R) oral tablets, 2014).
    2) Human reproductive studies of cabergoline have demonstrated congenital anomalies, abortions, low birth weights, premature births and stillbirths (Colao et al, 2008; Rains et al, 1995). Cabergoline should be administered during pregnancy only if clearly needed (Prod Info DOSTINEX(R) oral tablets, 2014).
    B) ABORTION
    1) In a 12-year, prospective, observational study, pregnancy outcomes were analyzed among women who were treated with cabergoline at the time of conception and/or during pregnancy (n=380). Fifty-one pregnancies were not included due to conception dates of more than 6 weeks after the last cabergoline dose (n=16), cabergoline administered on the delivery date (n=1), and data not available primarily due to ongoing pregnancy at study end or loss to follow-up (n=34) leaving 329 pregnancies with known outcomes. Among the 329 pregnancies, 71 (22%) were abortions. Voluntary, spontaneous and therapeutic abortions accounted for 31 (44%), 30 (42%), and 9 (13%) of the total abortions, respectively, with an unknown status for one. The 9 therapeutic abortions resulted from umbilical strangulation (n=1), tubular pregnancy (n=1), fetal death (n=1), and fetal malformations (n=6) including 3 cases of Down syndrome and one case each of deformed legs, fetal hydrocephalus, and prune belly syndrome (Colao et al, 2008).
    2) In a study of cabergoline-associated pregnancies (n=199), the occurrence of spontaneous abortions with cabergoline therapy was 11.6% compared to 11% in the general population (Rains et al, 1995).
    C) LOW BIRTH WEIGHT
    1) In a 12-year, prospective, observational study, pregnancy outcomes were analyzed among women who were treated with cabergoline at the time of conception and/or during pregnancy (n=380). Birth weight was less than 2500 g in 17 (7%) of the 258 live-born infants (Colao et al, 2008).
    D) PREMATURE BIRTH
    1) In a 12-year, prospective, observational study, pregnancy outcomes were analyzed among women who were treated with cabergoline at the time of conception and/or during pregnancy (n=380). Preterm deliveries (gestational period less than or equal to 37 wks) occurred in 45 (18%) of the 250 live deliveries (Colao et al, 2008).
    E) STILLBIRTH
    1) In a 12-year, prospective, observational study, pregnancy outcomes were analyzed among women who were treated with cabergoline at the time of conception and/or during pregnancy (n=380). Of the 258 deliveries, there were 4 stillbirths (2%) and 4 in which the status of delivery was unknown (Colao et al, 2008).
    F) ANIMAL STUDIES
    a) MICE: Maternotoxicity was reported when mice were given doses of 8 mg/kg/day (approximately 55 times the maximum recommended human dose) during the period of organogenesis (Prod Info DOSTINEX(R) oral tablets, 2014).
    2) RATS: An increase in post-implantation embryofetal losses was reported when rats were given doses of 0.012 mg/kg/day (approximately 1/7 the maximum recommended human dose) during the period of organogenesis, possibly due to the prolactin inhibitory properties of cabergoline in rats. (Prod Info DOSTINEX(R) oral tablets, 2014).
    3) RABBITS: Maternotoxicity, characterized by a loss of body weight and decreased food consumption, was reported when rabbits were given doses of 0.5 mg/kg/day (approximately 19 times the maximum recommended human dose) during the period of organogenesis (Prod Info DOSTINEX(R) oral tablets, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known whether cabergoline is excreted into human breast milk and the potential for adverse effects in the nursing infant from exposure to the drug are unknown. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue the drug or discontinue nursing, taking into consideration the importance of the drug to the mother. Because the prolactin-lowering action of cabergoline suggests that it will interfere with lactation, cabergoline should not be administered to women postpartum who are breast feeding or who are planning to breast feed (Prod Info DOSTINEX(R) oral tablets, 2014).
    B) ANIMAL STUDIES
    1) RATS: In animal studies, rats given doses higher than 0.003 mg/kg/day (approximately 1/28 the maximum recommended human dose) from 6 days before parturition and throughout lactation inhibited growth and caused death of offspring due to decreased milk secretion (Prod Info DOSTINEX(R) oral tablets, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) FEMALE RATS: Inhibited conception was observed when female rats were given a dose of 0.003 mg/kg/day (approximately 1/28 the maximum recommended human dose) prior to and throughout the mating period (Prod Info DOSTINEX(R) oral tablets, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor blood pressure in symptomatic patients.
    B) Monitor for signs of dyskinesias.
    C) Monitor serum electrolytes in patients with significant vomiting.
    D) Obtain a chest x-ray in symptomatic patients.
    E) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Methods

    A) CHROMATOGRAPHY
    1) A high-performance liquid chromatography with electrochemical detection technique was described for determination of cabergoline in plasma and urine. Cabergoline demonstrates poor UV absorption and a lack of fluorescence, therefore it is necessary to use electrochemical detection coupled with HPLC. The lowest limit of quantitation, using this method was 0.25 and 0.30 ng/mL in plasma and urine, respectively (Pianezzola et al, 1992).
    2) Radio-thin layer chromatography (TLC) analysis was used to identify radiolabeled cabergoline and its metabolites in the urine following oral doses (Cocchiara & Benedetti, 1992).
    B) IMMUNOASSAY
    1) A radioimmunoassay technique was used in several patients for quantitative analyses of cabergoline in urine and plasma (Andreotti et al, 1995; Persiani et al, 1994).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe symptoms despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Monitor blood pressure in symptomatic patients.
    B) Monitor for signs of dyskinesias.
    C) Monitor serum electrolytes in patients with significant vomiting.
    D) Obtain a chest x-ray in symptomatic patients.
    E) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Orthostatic hypotension is frequently reported with cabergoline therapy and may occur following initial doses greater than 1 mg. Patients with mild orthostatic hypotension can be treated by remaining prone. Those who remain hypotensive can be treated with IV fluids. Correct any significant fluid and/or electrolyte abnormalities in patients with severe vomiting.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine, if unresponsive to fluids.
    B) MONITORING OF PATIENT
    1) Monitor blood pressure in symptomatic patients.
    2) Monitor for signs of dyskinesias.
    3) Monitor serum electrolytes in patients with significant vomiting.
    4) Obtain a chest x-ray in symptomatic patients.
    5) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

Enhanced Elimination

    A) HEMODIALYSIS
    1) It is unknown if hemodialysis would be effective in overdose.

Range Of Toxicity

Summary

    A) TOXICITY: A specific minimum toxic dose of cabergoline has not been established.
    B) THERAPEUTIC DOSE: ADULT: For hyperprolactinemic disorders, the recommended initial dose is 0.25 mg orally twice weekly. Based on the patient's serum prolactin level, the dose may be increased in increments of 0.25 mg twice weekly every 4 weeks, up to a MAX dose of 1 mg orally twice weekly. PEDIATRIC: Safety and efficacy have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) ORAL TABLETS
    1) HYPERPROLACTINEMIA: The recommended dose is 0.25 mg twice a week, titrated up to a maximum of 1 mg twice a week (Prod Info DOSTINEX(R) oral tablets, 2014).
    7.2.2) PEDIATRIC
    A) ORAL TABLETS
    1) Safety and efficacy in the pediatric population has not been established (Prod Info DOSTINEX(R) oral tablets, 2014).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)MOUSE:
    1) Greater than 400 mg/kg (RTECS, 2003)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Cabergoline is a long-acting dopaminergic agonist (Jori et al, 1990; Melis et al, 1987; Pontiroli et al, 1987; Ferrari et al, 1986) which occupies dopaminergic receptors in the pituitary gland to inhibit prolactin secretion(Prod Info Dostinex (R), 1999). The drug has been demonstrated to possess high affinity for dopamine D2 receptors, with an in vitro potency similar to bromocriptine and pergolide(Lera et al, 1990; di Salle et al, 1983).
    B) In receptor-binding studies, cabergoline has been shown to have low affinity for dopamine D1, alpha-1 and alpha-2 adrenergic, and 5-HT1- and 5-HT2-serotonin receptors(Prod Info Dostinex (R), 1999).

Physicochemical

Physical Characteristics

    A) Cabergoline is a white powder soluble in ethyl alcohol and chloroform, slightly soluble in 0.1 N hydrochloric acid, very slightly soluble in n-hexane, and insoluble in water(Prod Info Dostinex (R), 1999).

Molecular Weight

    A) 451.6 (Sweetman, 2003)

References

General Bibliography

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