Pergolide (Systemic)

VA CLASSIFICATION
Primary: CN500

Commonly used brand name(s): Permax.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antidyskinetic (dopamine agonist)—

Indications

Accepted

Parkinsonism (treatment adjunct)—Pergolide is indicated, as an adjunct to levodopa or levodopa/carbidopa therapy, for treatment of the signs and symptoms of idiopathic or postencephalitic Parkinson's disease to allow achievement of symptomatic relief with lower doses of levodopa or levodopa/carbidopa. ^{{01} {03} {05} {12} {13} {14}}

[Restless legs syndrome (treatment) ]¹—Pergolide is indicated for the treatment of restless legs syndrome.^{{19}{20}{21}{22}{23}{24}{25}{26}{27}}

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Pergolide is a semisynthetic ergot alkaloid derivative ^{{02} {05}}
Molecular weight—
    410.59 ^{17}

Mechanism of action/Effect:

Pergolide is a potent dopamine receptor agonist that directly stimulates post-synaptic dopamine receptors (at both D ₁ and D ₂ receptor sites) in the nigrostriatal system. Unlike bromocriptine, but similar to apomorphine and lysuride, the postsynaptic dopamine agonist properties are independent of presynaptic dopamine synthesis or stores. ^{{01} {02} {05}}


Other actions/effects:

Inhibits secretion of prolactin; causes transient rise in serum concentration of growth hormone in normal patients while in patients with acromegaly it causes a decrease; causes decrease in serum concentrations of luteinizing hormone (LH). ^{{01} {02} {05}}

Absorption:

Significant amount may be absorbed (at present, data on systemic bioavailability is insufficient). ^{01}

Protein binding:

Very high (approximately 90%). ^{01}

Elimination:
    Primarily renal (approximately 55% of a radionuclide labeled dose). However, approximately 5% is excreted via expired carbon dioxide.
^{18}

Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to other ergot derivatives may be sensitive to this medication also. ^{01}

Carcinogenicity

Uterine neoplasms in rats and mice, endometrial adenomas and carcinomas in rats,and endometrial sarcomas in mice, occurred with doses as high as 340 and 12 times (in mice and rats, respectively) the maximum human oral dose. It is believed that this was due to the high estrogen /progesterone ratio that may occur in rodents as a result of inhibition of prolactin secretion. Human data are not available. ^{01}

Mutagenicity

Pergolide generated a weak mutagenic response in the mammalian cell-point-mutation assay.(in cultured L5178Y cells); other assays, including a DNA repair assay, an Ames bacterial mutation assay, and a hamster bone chromosome alteration determination, generated a mutagenic-negative response .Human-related studies are currently unavailable.

Pregnancy/Reproduction
Fertility—
In a single study of male and female mice, fertility was preserved at dosage levels 0.6 and 1.7 mg/kg/day, but was impaired at 5.6mg/kg/day. The relevance of this data to humans is currently unknown.

Pregnancy—
Adequate and well-controlled studies in humans have not been done. In pre-market release studies of women treated with pergolide for endocrine disorders, congenital abnormalities were associated with 6 out of 39 pregnancies. Although a causal relationship has yet to be established, this drug should be used only with caution during pregnancy.

Reproduction studies in mice and rabbits with doses as high as 375 and 133 times, respectively, the maximum human dose administered in clinical trials (6 mg/day) have not shown that pergolide causes adverse effects on the fetus. ^{01}

FDA Pregnancy Category B. ^{01}

Breast-feeding

Pergolide may inhibit lactation. Excretion of pergolide in breast milk has not yet been confirmed. However, since human milk excretion occurs with many drugs, a decision should be made regarding the benefit/risk of continuing the drug, compared with that of continuing nursing by the mother. ^{01}

Pediatrics

No published pediatrics-specific information is available. Safety and efficacy have not been established. ^{01}


Geriatrics


Studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of pergolide in the elderly. ^{01}


Dental

Pergolide may decrease or inhibit salivary flow, thus contributing to the development of caries, periodontal disease, oral candidiasis, and discomfort. ^{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: Drugs known to affect protein binding should be used with caution, due to pergolide's preferential binding with plasma protein.^{18}
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Droperidol or
Haloperidol or
Loxapine or
Methyldopa or
Metoclopramide or
Molindone or
Papaverine or
Phenothiazines or
Reserpine or
Thioxanthenes    (dopamine antagonists may decrease the effectiveness of pergolide ^{01})


Hypotension-producing medications, other (See Appendix II )    (concurrent use may result in additive hypotensive effects)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Plasma growth hormone concentrations    (may be transiently increased in individuals with normal concentrations; paradoxically reduced in patients with acromegaly ^{{01} {02}})


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 problem exists:
» Sensitivity to pergolide or other ergot alkaloids ^{01}
Risk-benefit should be considered when the following medical problems exist
Cardiac dysrhythmias    (increased risk of atrial premature contractions and sinus tachycardia ^{{01} {06} {11}})


Psychiatric disorders    (pre-existing states of confusion and hallucinations may be exacerbated ^{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    (pergolide commonly decreases or less frequently increases blood pressure ^{01})


Note: Specific laboratory tests are not deemed essential^{18}. Periodic, routine laboratory screenings are recommended^{18}.




Side/Adverse Effects
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 more frequent
    
Anemia (unusual tiredness or weakness)
    
CNS effects ^{{01} {04} {05} {07} {08} {09} {13}}, including anxiety^{18}
confusion,^{18}
dyskinesias^{18} ( uncontrolled movements of the body, such as the face, tongue, arms, hands, head, and upper body), hallucinations^{18} (seeing, hearing, or feeling things that are not there), insomnia^{18} ( trouble in sleeping)
    
urinary tract infection ^{01} (bloody or cloudy urine; difficult or painful urination; frequent urge to urinate)
    
visual disturbances, including diplopia^{18} (visual changes; double vision )

Incidence less frequent
    
Hypertension ^{18} (dizziness; headache)
    
peripheral edema^{18} (swelling in hands and legs.)

Incidence rare
    
Cerebrovascular hemorrhage ^{01}{18} (severe or continuing headache; seizures; vision changes, such as blurred vision or temporary blindness; sudden weakness)
    
, myocardial infarction ^{01}{18} (severe chest pain; fainting; fast heartbeat; increased sweating; continuing or severe nausea and vomiting; nervousness; unexplained shortness of breath; weakness)
    
neuroleptic malignant syndrome (NMS)^{18} (difficult or unusually fast breathing [difficulty in breathing]; fast heartbeat or irregular pulse; high fever; high or low [irregular] blood pressure; increased sweating ; loss of bladder control; severe muscle stiffness; seizures; unusual tiredness or weakness; unusually pale skin)
    
serous inflammation and fibrosis, including pleuritis^{18} (chest pain; chills; dry cough; fever; troubled breathing ), pleural infection^{18} (chest pain; cough; fever; troubled breathing ), pleural fibrosis^{18} (chest pain; cough; shortness of breath), pericarditis^{18} (anxiety; chest pain; chills; cough; fever; troubled breathing ; weakness), pericardial effusion^{18} (chest pain; troubled breathing), retroperitoneal fibrosis^{18} (abdominal pain or pressure; decrease in flow of urine; pain in side or lower back)

Note: Neuroleptic malignant syndrome has been associated with the rapid reduction, withdrawal, or change of dosage in pergolide, and in other anti-Parkinsonian drugs^{18}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Dyspepsia^{18} (heartburn)
    
constipation ^{01}{18}
    
dizziness^{01}
    
drowsiness^{18}
    
influenza-like symptoms ^{01}{18} (headache, ; muscle pain; runny nose; chest congestion)
    
hypotension ^{{05} {09} {13}} (dizziness or lightheadedness, especially when getting up from a lying or sitting position)
    
lower back pain ^{01}
    
nausea ^{{01} {04} {05} {08} {13}}
    
rhinitis ^{{01} {04}} (runny or stuffy nose)
    
weakness ^{01}
Note: Approximately 10% of patients experience orthostatic hypotension during initial treatment. Tolerance usually develops with gradual dosage titration. ^{{01} {04}}



Incidence less frequent ^{01}
    
Diarrhea^{18}
    
dryness of mouth^{18}
    
facial edema^{18} ( swelling of the face)
    
anorexia^{18} (loss of appetite)
    
vomiting^{18}





Overdose
For specific information on the agents used in the management of pergolide overdose, see:    • Charcoal, Activated (Oral-Local) monograph; and/or
   • Phenothiazines (Systemic) monograph.


For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Treatment of overdose
Treatment is symptomatic and supportive, with possible utilization of the following: ^{01}

To decrease absorption—Administration of activated charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may expedite the elimination of ingested pergolide prior to absorption.

Specific treatment—Antiarrhythmic medication, if necessary. Phenothiazine or other neuroleptic agent, to treat CNS stimulation.

Monitoring—Monitoring of cardiac function.

Supportive care—Maintenance of arterial blood pressure, and protection of the patient's airway. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Pergolide (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to pergolide or other ergot alkaloids





Breast-feeding—May prevent lactation in mothers who intend to breast-feed





Dental—Reduced salivary flow may contribute to dental problems

Proper use of this medication
Taking with meals to reduce gastric effects

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» 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

Dizziness may be more likely to occur after initial doses; taking first dose at bedtime or while lying down; getting up slowly from sitting or lying position

Possible dryness of mouth; using sugarless gum or candy, ice, or saliva substitute for relief; checking with physician or dentist if dry mouth continues for more than 2 weeks

Checking with physician before reducing dosage or discontinuing medication


Side/adverse effects
Signs of potential side effects, especially anemia, CNS effects, urinary tract infection, visual disturbances, hypertension, peripheral edema, cerebrovascular hemorrhage, myocardial infarction, neuroleptic malignant syndrome, and serous inflammation and fibrosis


General Dosing Information
Titrated dosage is necessary to achieve the individual therapeutic blood concentration requirements and to minimize the risk of side effects.

Nausea and dizziness associated with initiation of pergolide therapy usually resolve with continued therapy; however, incidence and severity of these side effects may be reduced with a decrease in pergolide dose. ^{{05} {13}} Dizziness and nausea may be better tolerated by administering the initial dose at bedtime or while lying down. Also, administration of pergolide with food may alleviate the nausea

Abrupt change in pergolide dosage (reduction or withdrawal) has been associated with a symptom complex similar to neuroleptic malignant syndrome. Caution should be exercised whenever a change is required in pergolide dosage.


Oral Dosage Forms

Note: The dosing and strengths of the dosage forms available are expressed in terms of pergolide base, not the mesylate salt.


PERGOLIDE MESYLATE TABLETS

Usual adult and adolescent dose
Parkinsonism
Oral, 50 mcg (0.05 mg) (base) a day for the first two days; the dosage being increased gradually by 100 or 150 mcg (0.1 or 0.15 mg) (base) every third day over the next twelve days of therapy. Afterwards, the dose may be increased by 250 mcg (0.25 mg) (base) every third day until optimum therapeutic effect is achieved^{01}.


Note: Usually administered in divided doses three times a day. ^{01}
During dosage titration of pergolide the concurrent dose of levodopa or levodopa/carbidopa may be decreased with caution according to clinical response^{01}.
Clinical studies have documented a mean pergolide dosage of 3 mg per day^{18}. Concurrent administration of levodopa/carbidopa averaged 650 mg/day^{18}. Efficacy of pergolide dosage in excess of 5 mg/day has not been systematically evaluated^{18}.

[ Restless legs syndrome (treatment)]¹
Oral, 50 mcg (0.05 mg) (base) a day given two hours before bedtime. Dosage may be increased by 0.05 mg daily until optimum therapeutic effect is achieved.^{{19}{20}{21}{22}{23}{24}{25}{26}{27}}


Usual adult prescribing limits
5 mg daily^{01}.

Usual pediatric dose
Safety and efficacy have not been established^{01}.

Usual geriatric dose
See Usual adult and adolescent dose.

Strength(s) usually available
U.S.—


50 mcg (0.05 mg) (base) (Rx) [Permax (scored) (croscarmellose sodium) (iron oxide ) (lactose) (magnesium stearate) (methionine) ( povidone)]


250 mcg (0.25 mg) (base) (Rx) [Permax (scored) (croscarmellose sodium) (iron oxide ) (lactose) (magnesium stearate) (povidone) ( FD&C Blue No. 2)]


1 mg (base) (Rx) [Permax (scored) ( croscarmellose sodium) (iron oxide) (lactose) (magnesium stearate) (povidone)]

Canada—


50 mcg (0.05 mg) (base) (Rx) [Permax (scored) (croscarmellose sodium) (iron oxide yellow) (lactose) (magnesium stearate) (povidine) ( FD &C Blue No. 2 Aluminum Lake)]


250 mcg (0.25 mg) (base) (Rx) [Permax (scored) (croscarmellose sodium) (iron oxide yellow) (lactose) (l-methionine ) (magnesium stearate) ( povidine)]


1 mg (base) (Rx) [Permax (scored) ( croscarmellose sodium) (iron oxide red pure) (lactose) (magnesium stearate) (povidine)]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer^{01}.

Auxiliary labeling:
   • May cause drowsiness.
   • May cause dizziness

Revised: 01/07/2003

References

1. Permax package insert, Eli Lilly, 01/20/89.
   

2. Martindale, the extra pharmacopeia. 29th ed. London: The Pharmaceutical Press, 1989: 1021.
   

3. Goetz CG, Tanner CM, Glantz RH, et al. Chronic agonist therapy for Parkinson"s disease: A 5-year study of bromocriptine and pergolide. Neurology 1985 May; 35(5): 749-51.
   

4. Janovick J. Neurology 1985 May; 35(5): 296.
   

5. Olanow CW, Alberts MJ. Double-blind controlled study of pergolide mesylate in the treatment of Parkinson"s disease. Clin Neuropharmacol 1987; 10(2): 178-85.
   

6. Tanner CM, Chablani R, Goetz CG, et al. Pergolide mesylate: lack of cardiac toxicity in patients with cardiac disease. Neurology 1985 Jun; 35(6): 918-21.
   

7. Stern Y, Mayeux R, Ilson J, et al. Pergolide therapy for Parkinson"s disease: neurobehavioral changes. Neurology 1984 Feb; 34(2): 201-4.
   

8. Jeanty P, Van den Kerchove M, Lowenthal A, et al. Pergolide therapy in Parkinson"s disease. J Neurol 1984; 231(3): 148-52.
   

9. Jankovic J. Controlled trial of pergolide mesylate in Parkinson"s disease and progressive supranuclear palsy. Neurology 1983 Apr; 33(4): 505-7.
   

10. Lieberman AN, Neophytides A, Leibowitz M, et al. Comparative efficacy of pergolide and bromocriptine in patients with advanced Parkinson"s disease. Adv Neurol 1983; 37: 95-108.
    

11. Leibowitz M, Lieberman AN, Neophytides A, et al. The effects of pergolide on the cardiovascular system of 40 patients with Parkinson"s disease. Adv Neurol 1983; 37: 121-30.
    

12. Lang AE. Update on dopamine agonists in Parkinson"s disease: beyond bromocriptine. Can J Neurol Sci 1987 Aug; 14(3 Suppl): 474-82.
    

13. Lieberman AN, Goldstein M, Gopinathan G, et al. D ₁ and D ₂ agonists in Parkinson"s disease. Can J Neurol Sci 1987 Aug; 14(3 Suppl): 466-73.
    

14. Lieberman AN, Gopinathan G, Neophytides A, et al. Management of levodopa failures: the use of dopamine agonists. Clin Neuropharmacol 1986; 9(Suppl 2): S9-21.
    

15. Factor SA, Sanchez-Ramos JR, Weiner WJ. Parkinson"s disease: An open label trial of pergolide in patients failing bromocriptine therapy. J Neurol Neurosurg Psychiatry 1988 Apr; 51(4): 529-33.
    

16. Permax package insert (Lilly—Canada), Rev 6/19/91, Rec 4/6/92.
    

17. USAN. Rockville, MD: The U.S. Pharmacopeia, 1989.
    

18. Permax package insert
    
    
    
    (Elan—US), Rev 2/4/99, Rec 9/20/99.
    

19. Reviewer's consensus of ballot of 11/30/2002.
    

20. Staedt J, Wassmuth F, Ziemann U, et al. Pergolide: treatment of choice in restless legs syndrome (RLS) and nocturnal myoclonus syndrome (NMS). A double-blind randomized crossover trial of pergolide versus L-Dopa. J Neural Trans 1997;104(4–5):461–8.
    

21. Staedt J, Hunerjager H, Ruther E, et al. Pergolide: treatment of choice in Restless Legs Syndrome (RLS) and Nocturnal Myoclonus Syndrome (NMC). Longterm follow up on pergolide. Short communication. J Neural Transm 1998;105 (2–3):265–8.
    

22. Silber MH, Shepard JW Jr, Wisby JA. Pergolide in the management of restless legs syndrome: an extended study. Sleep 1997;20(10):878–82.
    

23. Noel S, Korri H, Vandenheyden JE. Low dosage of pergolide in the treatment of restless legs syndrome. Acta Neurol Belg 1998;98(1):52–3.
    

24. Winkelman J, Wetter TC, Stiasny K, et al. Treatment of restless legs syndrome with pergolide- an open clinical trial. Mov Disord 1998;13(3):566–9.
    

25. Earley CJ, Yaffee JB, Allen RP. Randomized, double-blind, placebo-controlled trial of pergolide in restless legs syndrome. Neurology 1998;51(6):1599–602.
    

26. Wetter TC, Stiasny K, Winkelmann J, et al. A randomized controlled study of pergolide in patients with restless legs syndrome. Neurology1999;52(5):944–50.
    

27. Penzel T, Brandenberg U, Peter JH, et al. A new design of a polysomnography-based multi-center treatment study for the restless legs syndrome. Clin Neurophysiol 2002;113(4):571–8.