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PERGOLIDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Pergolide is an ergoline derivative and selective dopamine agonist with a high affinity for the D2 receptor site and a lesser affinity for the D1 receptor site.

Specific Substances

    1) 8-beta-Methylthiomethyl-6-propylergoline methanesulphonate
    2) Methyl (8R,10R)-6-propylergolin-8-ylmethyl sulphide mesylate
    3) LY-127809
    1.2.1) MOLECULAR FORMULA
    1) C19-H26-N2-S,CH4-O3-S

Available Forms Sources

    A) USES
    1) WITHDRAWAL FROM MARKET - As of March 2007, the FDA announced that the manufacturer and distributor of pergolide will withdraw the product from the market due to an increased risk of serious heart valve damage. In two new studies, patients with Parkinson's disease treated with pergolide had an increased risk of serious damage to their heart valves as compared to patients who did not receive the drug (US Food and Drug Administration, 2007).
    a) In the interim, the manufacturer is working with the FDA to see if the drug may be available to select patients who are currently taking pergolide who were previously unable to switch successfully to a different treatment. However, healthcare professionals should consider all treatment options because in the future the drug may not be available.
    2) Pergolide is indicated as adjunctive treatment in the management of the signs and symptoms of Parkinson's disease (Prod Info Permax(R), 2001).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) Somnolence, dyskinesias, nausea, dry mouth, constipation, and hallucinations may frequently occur following therapeutic administration of pergolide.
    a) WITDRAWAL FROM MARKET - As of March 2007, the FDA announced that the manufacturer and distributor of pergolide will withdraw the product from the market due to an increased risk of serious heart valve damage. It may be available on a limited basis to select patients.
    B) WITH POISONING/EXPOSURE
    1) Overdose information is limited. Spontaneous vomiting, hypotension, sweating, nausea, dizziness, agitation, dyskinesias, and hallucinations have been reported following overdose ingestions. No deaths have been reported. Seizures and CNS stimulation have occurred in animal toxicity studies, but have not yet been reported in humans.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Orthostatic hypotension and palpitations are common adverse effects with pergolide therapy.
    B) WITH POISONING/EXPOSURE
    1) Hypotension and palpitations may occur following pergolide overdose.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Dyskinesias and somnolence have been commonly reported with pergolide therapy.
    B) WITH POISONING/EXPOSURE
    1) Involuntary movement, agitation, and paresthesias have been reported in overdose. Seizures have occurred in animal overdose models.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Nausea, constipation, and dry mouth frequently occur following therapeutic administration of pergolide.
    B) WITH POISONING/EXPOSURE
    1) Nausea and vomiting are common overdose effects.
    0.2.10) GENITOURINARY
    A) WITH THERAPEUTIC USE
    1) Retroperitoneal fibrosis has been reported in several patients following long-term pergolide therapy.
    0.2.20) REPRODUCTIVE
    A) Pergolide is classified as FDA pregnancy category B.

Laboratory Monitoring

    A) Monitor blood pressure and ECG in symptomatic patients.
    B) Monitor for CNS signs of dyskinesias or seizures.
    C) Monitor fluid and electrolyte levels in patients experiencing severe and/or prolonged vomiting.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Pergolide overdose information is limited. Treatment is symptomatic and supportive.
    B) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    C) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    D) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.

Range Of Toxicity

    A) A specific minimum toxic dose of pergolide has not been established.
    B) Pergolide overdose ingestions of 7 mg and 60 mg in adults have resulted in palpitations, hypotension, ventricular extrasystoles, and agitation.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) Somnolence, dyskinesias, nausea, dry mouth, constipation, and hallucinations may frequently occur following therapeutic administration of pergolide.
    a) WITDRAWAL FROM MARKET - As of March 2007, the FDA announced that the manufacturer and distributor of pergolide will withdraw the product from the market due to an increased risk of serious heart valve damage. It may be available on a limited basis to select patients.
    B) WITH POISONING/EXPOSURE
    1) Overdose information is limited. Spontaneous vomiting, hypotension, sweating, nausea, dizziness, agitation, dyskinesias, and hallucinations have been reported following overdose ingestions. No deaths have been reported. Seizures and CNS stimulation have occurred in animal toxicity studies, but have not yet been reported in humans.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) DELAYED VISUAL LOSS - A 64-year-old female, with a 1-year history of progressively blurred vision, was diagnosed with a prolactin-secreting pituitary adenoma and began taking pergolide, 0.1 mg/day. Within several weeks after beginning pergolide therapy, the patient noticed marked improvement in her vision; however, 13 months after initiating pergolide treatment, the patient’s visual acuity began to deteriorate. After decreasing the pergolide dose to 0.05 mg/day, the patient’s visual acuity gradually returned to normal (Chuman et al, 2002).
    2) MYDRIASIS has been reported in animal studies following treatment with pergolide eyedrops (Grant & Schuman, 1993).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Orthostatic hypotension and palpitations are common adverse effects with pergolide therapy.
    B) WITH POISONING/EXPOSURE
    1) Hypotension and palpitations may occur following pergolide overdose.
    3.5.2) CLINICAL EFFECTS
    A) HEART VALVE DISORDER
    1) WITH THERAPEUTIC USE
    a) WITHDRAWAL FROM MARKET - As of March 2007, the FDA announced that the manufacturer and distributor of pergolide will withdraw the product from the market due to an increased risk of serious heart valve damage. In two new studies, patients with Parkinson's disease treated with pergolide had an increased risk of serious damage to their heart valves as compared to patients who did not receive the drug (US Food and Drug Administration, 2007).
    B) LOW BLOOD PRESSURE
    1) WITH THERAPEUTIC USE
    a) Orthostatic hypotension and palpitations are common with therapeutic administration of pergolide (Prod Info Permax(R), 2001).
    b) INCIDENCE - Orthostatic hypotension has been reported in 10% of patients (n=189) receiving pergolide during a clinical trial as compared with 7% of patients (n=187) receiving placebo (Prod Info Permax(R), 2001).
    c) CASE REPORT- Severe hypotension (60 mmHg/palpitation) occurred in a 47-year-old male four hours after receiving the first dose of pergolide, 0.05 mg at bedtime, for treatment of restless legs syndrome. The patient was also taking lisinopril, 10 mg every morning. With supportive care, the patient completely recovered approximately 16 hours post-ingestion. It was unclear if the severe hypotensive reaction was due to hypersensitivity to the pergolide or an interaction between pergolide and lisinopril (Kando et al, 1990).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT - An intentional overdose of 60 mg of pergolide and an inadvertent overdose of 7 mg resulted in hypotension (Prod Info Permax(R), 2001).
    C) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) One patient experienced an increase in premature ventricular contractions while on pergolide therapy (Kurlan et al, 1985). A 72-year-old man with a first-degree block on baseline electrocardiogram showed new frequent premature ventricular contractions on a repeat electrocardiogram. The patient had been on oral pergolide 0.4 mg/day for 17 days, and this was the only new drug to his therapy. The only other chronic medication mentioned was levodopa, and its dose was not increased. A 24-hour Holter monitor showed normal sinus rhythm, approximately 800 episodes of Mobitz-type 1 heart block, frequent episodes of bradycardia with rates of 30 to 35 beats per minute, and approximately 3,700 premature ventricular contractions. The patient did not report any cardiac symptoms during the monitoring period. Upon discontinuation of pergolide, the premature ventricular contractions resolved.
    2) WITH POISONING/EXPOSURE
    a) Ventricular extrasystoles and palpitations were reported, in an adult, following inadvertent administration of 7 mg pergolide instead of the prescribed 0.7 mg (Prod Info Permax(R), 2001).
    D) PERICARDITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 67-year-old man with a history of Parkinson's disease and ischemic heart disease developed constrictive pericarditis after 11 months of pergolide treatment. Pergolide was added as adjuvant therapy to a regimen of levodopa and carbidopa. Pericardectomy showed the pericardium had a large area of thickening, calcification, and pericardial adhesions. Four weeks following surgery, the patient was readmitted to the hospital for bilateral pleural effusions. When pergolide administration was discontinued, the patient experienced a steady improvement in clinical status (Balanchandran et al, 2002).
    b) CASE REPORT - A 63-year-old man developed a mild anemia 2 years after pergolide was introduced and titrated to a maximum of 1 milligram (mg) per day. Within 14 months of the anemia, symptoms of exertional dyspnea and paroxysmal atrial fibrillation and signs of gross right ventricular failure were suspected to be caused by constrictive pericarditis, which diagnosis was confirmed with cardiac catheterization. Surgery revealed the heart encased in thick, calcified pericardium; total pericardectomy freed the vena cavae and brought an immediate fall in right atrial pressure to normal values (Shaunak et al, 1999).
    E) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) A tentative association between pergolide treatment and development of severe, regurgitant valvular heart disease was drawn from a series of 3 elderly patients in whom both echocardiographic and histologic examination of resected tricuspid, mitral, and aortic valves were consistent with changes seen with ergot- or fenfluramine-related valvulopathies. Pergolide exposure ranged from 3 to 7 years at dose levels between 1.5 and 6 mg daily. Two patients had been referred for evaluation of worsening dyspneic symptoms, edema, and weight gain, and the third for asymptomatic heart murmur. Severe tricuspid regurgitation was identified in all. One patient required tricuspid valve replacement and one patient underwent tricuspid, mitral, and aortic valve replacement. The third patient had pergolide discontinued and remained unchanged 3 months later.
    1) Systematic evaluation ruled against the 6 most common reasons for tricuspid valve replacement (rheumatic heart disease, congenital lesions, pulmonary hypertension, carcinoid syndrome, infective endocarditis, trauma) leaving iatrogenic (drug-induced) reasons as the most likely candidate (Pritchett et al, 2002).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPOTENSION
    a) Hypotension has occurred in animal studies of pergolide overdose (Prod Info Permax(R), 2001).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) FIBROSIS OF LUNG
    1) WITH THERAPEUTIC USE
    a) Pleuropulmonary fibrosis was reported in several patients following long-term pergolide therapy. Symptoms included dyspnea, fatigue, and a dry cough. In one patient, a chest CT scan showed extensive intrapulmonary fibrotic lesions on both sides with pleural thickening and pleural effusion. In three patients, histologic examination following a pleural biopsy showed non-specific fibrous inflammation. In the majority of patients, signs and symptoms improved following discontinuation of pergolide therapy. However, in one patient, cessation of pergolide therapy did not appear to result in clinical improvement or a resolution of radiologic findings (Tintner et al, 2005; Bleumink et al, 2002; Danoff et al, 2001; Shaunak et al, 1999).
    B) EDEMA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - Generalized edema was reported in a 71-year-old woman with a 10-year history of Parkinson's disease and who had been on pergolide therapy. The patient presented with increasing dyspnea and progressive leg edema. A chest CT scan revealed bilateral pleural effusion. The edema completely resolved seven days after discontinuation of pergolide therapy and with diuretic administration (Bianchi & Castiglioni, 2005).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Dyskinesias and somnolence have been commonly reported with pergolide therapy.
    B) WITH POISONING/EXPOSURE
    1) Involuntary movement, agitation, and paresthesias have been reported in overdose. Seizures have occurred in animal overdose models.
    3.7.2) CLINICAL EFFECTS
    A) DYSKINESIA
    1) WITH THERAPEUTIC USE
    a) Dyskinesias are a commonly reported adverse event with pergolide therapy (Prod Info Permax(R), 2001; Olanow & Alberts, 1986).
    b) INCIDENCE - Dyskinesias were reported in 62.4% of patients (n=189), who received pergolide during a clinical trial, as compared with 24.6% of patients (n=187) who received placebo (Prod Info Permax(R), 2001).
    2) WITH POISONING/EXPOSURE
    a) In overdoses, involuntary movements were noted. Agitation was reported in a patient who intentionally took 60 mg of pergolide (Prod Info Permax(R), 2001).
    B) PARESTHESIA
    1) WITH POISONING/EXPOSURE
    a) A patient who unintentionally took pergolide 14 mg/day for 23 days, instead of 1.4 mg, experienced severe involuntary movements and tingling in her arms and legs (Prod Info Permax(R), 2001).
    C) DROWSY
    1) WITH THERAPEUTIC USE
    a) Profound somnolence resulting in unplanned daytime sleep episodes has occurred in an increasing number of patients receiving non-ergot dopamine agonist treatment of Parkinson's disease, such as pergolide. As with other non-ergot agents, pergolide-induced somnolence appears to be a dose-dependent phenomenon, occurring at doses ranging between 3 and 5 milligrams daily. Somnolence symptoms have been reversible with dose reductions (Schlesinger & Ravin, 2003; Ferreira et al, 2000; Schapira, 2000).
    D) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Orthostatic dizziness or lightheadedness has been reported in several patients following therapeutic administration of pergolide and appears to be reversible with continued therapy (Olanow & Alberts, 1986; Kurlan et al, 1985).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SEIZURES
    a) Seizures were reported following intentional overdoses of pergolide in animal studies (Prod Info Permax(R), 2001).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Nausea, constipation, and dry mouth frequently occur following therapeutic administration of pergolide.
    B) WITH POISONING/EXPOSURE
    1) Nausea and vomiting are common overdose effects.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea may frequently occur with pergolide therapy (Olanow & Alberts, 1986; Kurlan et al, 1985).
    b) INCIDENCE - Nausea was reported in 24.3% of patients (n=189) receiving pergolide, during a clinical trial, as compared with 12.8% of patients (n=187) receiving placebo (Prod Info Permax(R), 2001).
    2) WITH POISONING/EXPOSURE
    a) Nausea and vomiting have occurred as overdose effects (Prod Info Permax(R), 2001).
    B) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation is a common adverse effect (Prod Info Permax(R), 2001).
    b) INCIDENCE - During a clinical trial, constipation was reported in 10.6% of patients (n=189) receiving pergolide as compared with 5.9% of patients (n=187) receiving placebo (Prod Info Permax(R), 2001).
    C) APTYALISM
    1) WITH THERAPEUTIC USE
    a) Dryness of mouth is a frequent adverse effect, with 3.7% of patients (n=189) experiencing dry mouth, following pergolide therapy during a clinical trial, as compared with < 1% of patients (n=187) receiving placebo (Prod Info Permax(R), 2001).
    D) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) INCIDENCE - Diarrhea was reported in 6.4% of patients (n=189), following therapeutic administration of pergolide during a clinical trial, as compared with 2.1% of patients (n=187) receiving placebo (Prod Info Permax(R), 2001).

Genitourinary

    3.10.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Retroperitoneal fibrosis has been reported in several patients following long-term pergolide therapy.
    3.10.2) CLINICAL EFFECTS
    A) RETROPERITONEAL FIBROSIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - Retroperitoneal fibrosis (RPF) was observed in an 83-year-old female who received a 2-year regimen of pergolide, 1 milligram 3 times daily for treatment of Parkinson's disease. The patient initially presented with marked ankle edema, accompanied by elevations in BUN and creatinine (90 mg/dL and 4.0 mg/dL, respectively). Computerized tomography revealed a plate-like pelvic mass enveloping both ureters; subsequent surgical biopsy confirmed the presence of a dense fibrosis consistent with RPF. Renal function stabilized following placement of bilateral ureteral stents and discontinuation of pergolide (Lund et al, 1999).
    b) CASE REPORT - A 61-year-old male developed edema of the left leg associated with urinary frequency, nocturia, and loin pain approximately 2 years after beginning pergolide therapy, 3 mg/day, for treatment of Parkinson’s disease. The patient’s ESR was elevated at 57 mm/h and mild impairment of renal function was present. A CT of the abdomen revealed severe left hydronephrosis and appearances consistent with retroperitoneal fibrosis. Despite withdrawal of pergolide, the patient developed an atrophic, non-functioning left kidney and required maintenance with low-dose steroids (Shaunak et al, 1999).
    c) CASE REPORT - Three years after beginning pergolide therapy as part of a regimen for Parkinson's disease which also included carbidopa/levodopa and selegiline, a 68-year-old female was admitted with decreased diuresis as part of her presentation. Abdominal computerized tomography revealed a fibrous mass surrounding the left kidney and ureter, with stenosis, requiring surgical correction. Following pergolide withdrawal, the patient experienced no further sequelae. Routine monitoring of both renal function and erythrocyte sedimentation rate was suggested as useful during ergot derivative therapy (Jimenez-Jimenez et al, 1995).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia has been reported following treatment with pergolide (Prod Info Permax(R), 2001; Shaunak et al, 1999).
    b) CASE REPORT - A 63-year-old man developed a mild anemia 2 years after pergolide was introduced and titrated to a maximum of 1 milligram (mg) per day. Within 14 months of the anemia, symptoms of exertional dyspnea and paroxysmal atrial fibrillation and signs of gross right ventricular failure were suspected to be caused by constrictive pericarditis, which diagnosis was confirmed with cardiac catheterization. Surgery revealed the heart encased in thick, calcified pericardium; total pericardectomy freed the vena cavae and brought an immediate fall in right atrial pressure to normal values(Shaunak et al, 1999).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) EDEMA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - Pergolide was added to a regimen of carbidopa plus levodopa in a 69-year-old female to control increasing dystonia. During dose titration, the patient developed bilateral facial edema. Pergolide was withdrawn and edema cleared over 2 weeks (Garcia et al, 1993).
    B) DISORDER OF SKIN
    1) WITH THERAPEUTIC USE
    a) There are several case reports of erythromelalgia in the lower extremities of parkinsonian patients on pergolide therapy (Monk et al, 1984; Olanow & Alberts, 1986). Erythromelalgia presented as a bilateral erythematous rash on the shins which was warm to the touch. Two cases occurred after at least one year of pergolide therapy at unreported doses (Monk et al, 1984). The patients felt the benefit from pergolide therapy outweighed the discomfort of the erythromelalgia and continued therapy. The other case occurred during a 24-week study period at a pergolide dose between 1.5 and 4.25 mg/day (Olanow & Alberts, 1986). Reduction of the pergolide dose in the latter case improved but did not eliminate the erythromelalgia.

Reproductive

    3.20.1) SUMMARY
    A) Pergolide is classified as FDA pregnancy category B.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Pergolide is classified as FDA pregnancy category B (Prod Info Permax(R), 2001).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known whether pergolide is excreted in human milk (Prod Info Permax(R), 2001).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor blood pressure and ECG in symptomatic patients.
    B) Monitor for CNS signs of dyskinesias or seizures.
    C) Monitor fluid and electrolyte levels in patients experiencing severe and/or prolonged vomiting.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Monitor blood pressure and ECG in symptomatic patients.
    B) Monitor for CNS signs of dyskinesias or seizures.
    C) Monitor fluid and electrolyte levels in patients experiencing severe and/or prolonged vomiting.

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) Pergolide overdose information is limited. In general, treatment is symptomatic and supportive.
    B) MONITORING OF PATIENT
    1) Monitor blood pressure and ECG in symptomatic patients.
    2) Monitor fluid and electrolyte levels in patients experiencing severe and/or prolonged vomiting.
    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).
    D) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Because pergolide is highly protein-bound, hemodialysis is not expected to be of benefit.

Range Of Toxicity

Summary

    A) A specific minimum toxic dose of pergolide has not been established.
    B) Pergolide overdose ingestions of 7 mg and 60 mg in adults have resulted in palpitations, hypotension, ventricular extrasystoles, and agitation.

Therapeutic Dose

    7.2.1) ADULT
    A) WITHDRAWAL FROM MARKET
    1) As of March 2007, the FDA announced that the manufacturer and distributor of pergolide will withdraw the product from the market due to an increased risk of serious heart valve damage. In two new studies, patients with Parkinson's disease treated with pergolide had an increased risk of serious damage to their heart valves as compared to patients who did not receive the drug (US Food and Drug Administration, 2007).
    2) GENERAL
    a) PARKINSON'S DISEASE - The initial recommended dose is 0.05 milligram for 2 days, then titrated up to a mean therapeutic dose of 3 milligrams/day (Prod Info Permax(R), 2001).
    7.2.2) PEDIATRIC
    A) GENERAL
    1) Safety and efficacy in the pediatric population has not been established (Prod Info Permax(R), 2001).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) A young adult developed vomiting, hypotension, and agitation following an intentional overdose of 60 milligrams (Prod Info Permax(R), 2001).
    2) An unintentional overdose of 7 milligrams in an adult resulted in palpitations, hypotension, and ventricular extrasystoles (Prod Info Permax(R), 2001).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 100 mg/kg (RTECS, 2003)
    B) LD50- (ORAL)MOUSE:
    1) 54 mg/kg (RTECS, 2003)
    C) LD50- (ORAL)RAT:
    1) 8400 mg/kg (RTECS, 2003)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Pergolide is a synthetic ergoline with very potent and long-acting dopamine agonist activity. Animal data suggest that the drug is a direct-acting dopamine agonist at the striatal dopamine receptors (Koller et al, 1980). Pergolide is both a D-1 and D-2 dopamine receptor agonist (Goldstein et al, 1980). It appears that only the D-2 sites show properties related to dopaminergic behavioral and endocrinological responses (Calne, 1980; Larsen & Calne, 1982). The reduced tonic stimulation of dopaminergic D-2 receptors located on intrastriatal cholinergic neurons is the most likely cause of the parkinsonian symptoms (Sethy, 1979; Scatton, 1982). Like other dopamine agonists, pergolide occupies dopaminergic receptors in the pituitary gland to inhibit prolactin secretion (Barbieri & Ryan, 1983).

Physicochemical

Physical Characteristics

    A) Pergolide is a white or almost white crystalline powder. It is slightly soluble in water, ethanol, and dichloromethane, very slightly soluble in acetone, and sparingly soluble in methanol (Sweetman, 2003).

Molecular Weight

    A) 314.5 (Budavari, 1996)

References

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