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In clinical trials, approximately 10 % of patients taking pergolide mesylate with l-dopa versus 7% taking placebo with l-dopa experienced symptomatic orthostatic and/or sustained hypotension, especially during initial treatment. With gradual dosage titration, tolerance to the hypotension usually develops. It is therefore important to warn patients of the risk, to begin therapy with low doses, and to increase the dosage in carefully adjusted increments over a period of 3 to 4 weeks (see DOSAGE AND ADMININSTRATION).
In controlled trials, pergolide mesylate with l-dopa caused hallucinosis in about 14% of patients as opposed to 3% taking placebo with l-dopa. This was of sufficient severity to cause discontinuation of treatment in about 3% of those enrolled; tolerance to this untoward effect was not observed.
In the placebo-controlled trial, 2 of 187 patients treated with placebo died as compared with 1 of 189 patients treated with pergolide mesylate. Of the 2,299 patients treated with pergolide mesylate in premarketing studies evaluated as of October 1988, 143 died while on the drug or shortly after discontinuing it. Because the patient population under evaluation was elderly, ill, and at high risk for death, it seems unlikely that pergolide mesylate played any role in these deaths, but the possibility that pergolide shortens survival of patients cannot be excluded with absolute certainty.
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%.
Serious Inflammation and Fibrosis
There have been rare reports of pleuritis, pleural effusion, cardiac valvulopathy involving one or more valves, pleural fibrosis, pericarditis, pericardial effusion or retroperitoneal fibrosis in patients taking pergolide. In some cases, symptoms or manifestations of cardiac valvulopathy improved after discontinuation of pergolide. Some patients had experienced similar events while taking the ergot derivative bromocriptine. Pergolide should be used with caution in patients with a history of these conditions, particularly those patients who experienced the events while taking ergot derivatives. Patients with a history of such events should be carefully monitored clinically and with appropriate radiographic and laboratory studies while taking pergolide.
Caution should be exercised when administering pergolide mesylate to patients prone to cardiac dysrhythmias.
In a study comparing pergolide mesylate and placebo, patients taking pergolide mesylate were found to have signifiscantly more episodes premature contractions (PACs) and sinus tachycardia.
The use of pergolide mesylate in patients on l-dopa may cause and/or exacerbate preexisting states of confusion and hallucinations (see WARNINGS) and preexisting dyskinesia. Also, the abrupt discontinuation of pergolide mesylate in patients receiving it chronically as an adjunct to l-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 l-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, with drawal of, or changes in antiparkinsonian therapy, including pergolide.
Information for Patients
Patients and their families should be informed of the common adverse consequences of the use of pergolide mesylate (see ADVERSE REACTIONS) and the risk of hypotension (see WARNINGS ). 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.
No specific laboratory tests are deemed essential for the management of patients on Permax (pergolide mesylate) . Periodic routine evaluation of all patients, however, is appropriate.
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. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding.
A 2-year carcinogenicity study was conducted in mice using dietary levels of pergolide mesylate 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 mesylate. 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 mesylate 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-point- 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-point-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 decressed prolactin levels.
Usage in Pregnancy
Pregnancy Category B: 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 mesylate.
There are, however, no adequate and well-controlled studies in pregnant women. Among women who received pergolide mesylate 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.
It is not known whether this drug is excreted in human milk. The pharmacologic action of pergolide mesylate suggests that it may interfere with lactation. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions to pergolide mesylate in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness in pediatric patients have not been established.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 12/8/2004
Additional Permax Information
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