Permax Information
Permax (Pergolide mesylate) Description
Permax (Pergolide mesylate) (Pergolide Tablets, USP) is an ergot derivative dopamine receptor agonist at both D and D receptor sites. Pergolide mesylate is chemically designated as 8β-[(Methylthio)methyl]-6-propylergoline monomethanesulfonate; the structural formula is as follows:
The empirical formula is CHNS∙CHOS, representing a molecular weight of 410.60.
Permax (Pergolide mesylate) is provided for oral administration in tablets containing 0.05 mg (0.159 µmol), 0.25 mg (0.795 µmol), or 1 mg (3.18 µmol) pergolide as the base. The tablets also contain croscarmellose sodium, iron oxide, lactose, magnesium stearate, and povidone. The 0.05 mg tablet also contains L-methionine, and the 0.25 mg tablet also contains FD&C Blue No. 2.
Permax (Pergolide mesylate) Clinical Pharmacology
Information on oral systemic bioavailability of pergolide is unavailable because of the lack of a sufficiently sensitive assay to detect the drug after the administration of a single dose. However, following oral administration of C radiolabeled pergolide, approximately 55% of the administered radioactivity can be recovered from the urine and 5% from expired CO, suggesting that a significant fraction is absorbed. Nothing can be concluded about the extent of presystemic clearance, if any.
Data on postabsorption distribution of pergolide are unavailable.
At least 10 metabolites have been detected, including N-despropylpergolide, pergolide sulfoxide, and pergolide sulfone. Pergolide sulfoxide and pergolide sulfone are dopamine agonists in animals. The other detected metabolites have not been identified and it is not known whether any other metabolites are active pharmacologically.
The major route of excretion is the kidney.
Pergolide is approximately 90% bound to plasma proteins. This extent of protein binding may be important to consider when pergolide is coadministered with other drugs known to affect protein binding.
Permax (Pergolide mesylate) Indications And Usage
Permax (Pergolide mesylate) is indicated as adjunctive treatment to levodopa/carbidopa in the management of the signs and symptoms of Parkinson's disease.
Evidence to support the efficacy of pergolide as an antiparkinsonian adjunct was obtained in a multicenter study enrolling 376 patients with mild to moderate Parkinson's disease who were intolerant to -dopa/carbidopa as manifested by moderate to severe dyskinesia and/or on-off phenomena. On average, the patients evaluated had been on -dopa/carbidopa for 3.9 years (range, 2 days to 16.8 years). The administration of pergolide permitted a 5% to 30% reduction in the daily dose of -dopa. On average, these patients treated with pergolide maintained an equivalent or better clinical status than they exhibited at baseline.
Permax (Pergolide mesylate) Contraindications
Pergolide is contraindicated in patients who are hypersensitive to this drug or other ergot derivatives.
Permax (Pergolide mesylate) Warnings
In particular, a case-by-case review of the clinical course of the patients who died failed to disclose any unique set of signs, symptoms, or laboratory results that would suggest that treatment with pergolide caused their deaths. Sixty-eight percent (68%) of the patients who died were 65 years of age or older. No death (other than a suicide) occurred within the first month of treatment; most of the patients who died had been on pergolide for years. A relative frequency of the causes of death by organ system are: Pulmonary failure/Pneumonia, 35%; Cardiovascular, 30%; Cancer, 11%; Unknown, 8.4%; Infection, 3.5%; Extrapyramidal syndrome, 3.5%; Stroke, 2.1%; Dysphagia, 2.1%; Injury, 1.4%; Suicide, 1.4%; Dehydration, 0.7%; Glomerulonephritis, 0.7%.
Permax (Pergolide mesylate) Precautions
Caution should be exercised when administering pergolide to patients prone to cardiac dysrhythmias.
In a study comparing pergolide and placebo, patients taking pergolide were found to have significantly more episodes of atrial premature contractions (APCs) and sinus tachycardia.
The use of pergolide in patients on -dopa may cause and/or exacerbate preexisting states of confusion and hallucinations () and preexisting dyskinesia. Also, the abrupt discontinuation of pergolide in patients receiving it chronically as an adjunct to -dopa may precipitate the onset of hallucinations and confusion; these may occur within a span of several days. Discontinuation of pergolide should be undertaken gradually whenever possible, even if the patient is to remain on -dopa.
A symptom complex resembling the neuroleptic malignant syndrome (NMS) (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy, including pergolide.
Raynaud’s Phenomenon
Pergolide can rarely cause Raynaud’s phenomenon.
Because pergolide may cause somnolence and the possibility of falling asleep during activities of daily living, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that pergolide therapy does not affect them adversely. Patients should be advised that if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., watching television, passenger in a car, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Due to the possible additive sedative effects, caution should also be used when patients are taking other CNS depressants in combination with pergolide.
Patients and their families should be informed of the common adverse consequences of the use of pergolide () and the risk of hypotension ().
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.
Patients should be advised to notify their physician if they are breast feeding an infant.
As with other dopamine agonists, compulsive self-rewarding behavior (e.g., pathologic gambling) and libido increase have been reported in patients receiving pergolide therapy.
Dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthines) or metoclopramide, ordinarily should not be administered concurrently with Permax (Pergolide mesylate) (a dopamine agonist); these agents may diminish the effectiveness of Permax (Pergolide mesylate) .
Because pergolide is approximately 90% bound to plasma proteins, caution should be exercised if pergolide is coadministered with other drugs known to affect protein binding.
A 2-year carcinogenicity study was conducted in mice using dietary levels of pergolide equivalent to oral doses of 0.6, 3.7, and 36.4 mg/kg/day in males and 0.6, 4.4, and 40.8 mg/kg/day in females. A 2-year study in rats was conducted using dietary levels equivalent to oral doses of 0.04, 0.18, and 0.88 mg/kg/day in males and 0.05, 0.28, and 1.42 mg/kg/day in females. The highest doses tested in the mice and rats were approximately 340 and 12 times the maximum human oral dose administered in controlled clinical trials (6 mg/day equivalent to 0.12 mg/kg/day).
A low incidence of uterine neoplasms occurred in both rats and mice. Endometrial adenomas and carcinomas were observed in rats. Endometrial sarcomas were observed in mice. The occurrence of these neoplasms is probably attributable to the high estrogen/progesterone ratio that would occur in rodents as a result of the prolactin-inhibiting action of pergolide. The endocrine mechanisms believed to be involved in the rodents are not present in humans. However, even though there is no known correlation between uterine malignancies occurring in pergolide-treated rodents and human risk, there are no human data to substantiate this conclusion.
Pergolide was evaluated for mutagenic potential in a battery of tests that included an Ames bacterial mutation assay, a DNA repair assay in cultured rat hepatocytes, an in vitro mammalian cell gene mutation assay in cultured L5178Y cells, and a determination of chromosome alteration in bone marrow cells of Chinese hamsters. A weak mutagenic response was noted in the mammalian cell gene mutation assay only after metabolic activation with rat liver microsomes. No mutagenic effects were obtained in the 2 other in vitro assays and in the in vivo assay. The relevance of these findings in humans is unknown.
A fertility study in male and female mice showed that fertility was maintained at 0.6 and 1.7 mg/kg/day but decreased at 5.6 mg/kg/day. Prolactin has been reported to be involved in stimulating and maintaining progesterone levels required for implantation in mice and, therefore, the impaired fertility at the high dose may have occurred because of depressed prolactin levels.
Reproduction studies were conducted in mice at doses of 5, 16, and 45 mg/kg/day and in rabbits at doses of 2, 6, and 16 mg/kg/day. The highest doses tested in mice and rabbits were 375 and 133 times the 6 mg/day maximum human dose administered in controlled clinical trials. In these studies, there was no evidence of harm to the fetus due to pergolide.
There are, however, no adequate and well-controlled studies in pregnant women. Among women who received pergolide for endocrine disorders in premarketing studies, there were 33 pregnancies that resulted in healthy babies and 6 pregnancies that resulted in congenital abnormalities (3 major, 3 minor); a causal relationship has not been established. Because human data are limited and because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Permax (Pergolide mesylate) Adverse Reactions
The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side-effect incidence rate in the population studied.
The following enumeration by organ system describes events in terms of their relative frequency of reporting in the data base. Events of major clinical importance are also described in the Warnings and Precautions sections.
The following definitions of frequency are used: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Permax (Pergolide mesylate) Overdosage
There is no clinical experience with massive overdosage. The largest overdose involved a young hospitalized adult patient who was not being treated with pergolide but who intentionally took 60 mg of the drug. He experienced vomiting, hypotension, and agitation. Another patient receiving a daily dosage of 7 mg of pergolide unintentionally took 19 mg/day for 3 days, after which his vital signs were normal but he experienced severe hallucinations. Within 36 hours of resumption of the prescribed dosage level, the hallucinations stopped. One patient unintentionally took 14 mg/day for 23 days instead of her prescribed 1.4 mg/day dosage. She experienced severe involuntary movements and tingling in her arms and legs. Another patient who inadvertently received 7 mg instead of the prescribed 0.7 mg experienced palpitations, hypotension, and ventricular extrasystoles. The highest total daily dose (prescribed for several patients with refractory Parkinson's disease) has exceeded 30 mg.
Management of overdosage may require supportive measures to maintain arterial blood pressure. Cardiac function should be monitored; an antiarrhythmic agent may be necessary. If signs of CNS stimulation are present, a phenothiazine or other butyrophenone neuroleptic agent may be indicated; the efficacy of such drugs in reversing the effects of overdose has not been assessed.
Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or charcoal.
There is no experience with dialysis or hemoperfusion, and these procedures are unlikely to be of benefit.
Permax (Pergolide mesylate) Dosage And Administration
Administration of Permax (Pergolide mesylate) should be initiated with a daily dosage of 0.05 mg for the first 2 days. The dosage should then be gradually increased by 0.1 or 0.15 mg/day every third day over the next 12 days of therapy. The dosage may then be increased by 0.25 mg/day every third day until an optimal therapeutic dosage is achieved.
Permax (Pergolide mesylate) is usually administered in divided doses 3 times per day. During dosage titration, the dosage of concurrent dopa/carbidopa may be cautiously decreased.
In clinical studies, the mean therapeutic daily dosage of Permax (Pergolide mesylate) was 3 mg/day. The average concurrent daily dosage of dopa/carbidopa (expressed as dopa) was approximately 650 mg/day. The efficacy of Permax (Pergolide mesylate) at doses above 5 mg/day has not been systematically evaluated. Doses of pergolide above 5 mg/day are not recommended ().
Permax (Pergolide mesylate) How Supplied
Tablets (modified rectangle shape, scored):
0.05 mg, ivory, debossed with A 024, in bottles of 30 (UC5336) — NDC 0187-0839-01
0.25 mg, green, debossed with A 025, in bottles of 100 (UC5337) — NDC 0187-0840-02
1 mg, pink, debossed with A 026, in bottles of 100 (UC5338) — NDC 0187-0841-02
Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].
Permax (Pergolide mesylate) is a registered trademark of Eli Lilly and Company, and licensed in the US to Valeant Pharmaceuticals International.
