PERMAX™
Pergolide mesylate 0.05 mg, 0.25 mg and 1 mg tablets
Presentation
Permax 0.05 mg tablets: Cream coloured cuboid scored tablets, containing pergolide mesylate equivalent to 0.05 mg (0.159 micromol) pergolide base.
Permax 0.25 mg tablets: Green coloured cuboid scored tablets, containing pergolide mesylate equivalent to 0.25 mg (0.795 micromol) pergolide base.
Permax 1.0 mg tablets: Lavender coloured cuboid scored tablets, containing pergolide mesylate equivalent to 1.0 mg (3.18 micromol) pergolide base.
Uses
Actions
Pergolide is an ergot derivative dopamine receptor agonist at D1, D2 and D3 receptor sites.
Pergolide lowers serum prolactin concentrations in humans. It also causes transient increase in serum concentrations of growth hormone and a decrease in serum concentrations of luteinizing hormone. In Parkinson's disease, pergolide is believed to exert its therapeutic effect by directly stimulating post-synaptic dopamine receptors in the corpus striatum.
Pharmacokinetic Properties
Studies in patients with Parkinson's disease have shown appreciable plasma concentrations 15 to 30 minutes after oral administration. Pergolide appears to be active at the pituitary within 30 minutes of oral dosing, as measured by time to attenuation of plasma prolactin levels. Complete suppression of prolactin occurs two hours post dose.
Pergolide is approximately 90% bound to plasma proteins. In humans, pergolide is metabolised extensively. At least 10 metabolites have been isolated including N-despropyl pergolide, pergolide sulfoxide, and pergolide sulfone. Some metabolites have not been identified. After oral administration of radio-labelled pergolide to healthy subjects, 55% of the radioactivity was excreted in urine. The major route of excretion is the kidney.
Therapeutic Indications
Permax is indicated as adjunctive treatment to levodopa/carbidopa in the management of the signs and symptoms of Parkinson's disease. During the clinical trials of pergolide, very few patients received either levodopa or levodopa/benserazide as adjunctive treatment with pergolide. Data from those few patients do not reveal any contraindications or unexpected trends regarding safety in patients with Parkinson's disease. The adverse event profile was the same as the events identified with the much larger clinical trial database of patients with Parkinson's disease taking the medicine combination of pergolide and levodopa/carbidopa.
Dosage and Administration
Permax tablets are intended for oral administration.
Adults
Administration of Permax should be initiated with a single daily dosage of 0.05 mg for the first two 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 is usually administered in divided doses three times per day. During dosage titration, the dosage of concurrent L-dopa/carbidopa may be cautiously decreased.
In clinical studies, the mean therapeutic daily dosage of Permax was 3 mg/day. The average concurrent daily dosage of L-dopa/carbidopa (expressed as L-dopa) was approximately 650 mg/day. The efficacy of Permax at doses above 5 mg/day has not been systematically evaluated. As with other dopamine agonists, Permax should be discontinued gradually.
Children
Safety and effectiveness have not been established.
Contraindications
Hypersensitivity to pergolide or other ergot derivatives.
Warnings and Precautions
Warnings
A symptom complex resembling the neuroleptic malignant syndrome (NMS) (characterised by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious aetiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy, including pergolide.
Patients should be warned to begin therapy with low doses and to increase the dosage in carefully adjusted increments over a period of three to four weeks to minimise the risk of symptomatic orthostatic or postural hypotension and/or sustained hypotension. With gradual dose titration, tolerance to hypotension usually develops.
Hallucinations are known to be associated with dopamine agonist and levodopa treatment. In controlled trials of pergolide with levodopa, 3% of patients discontinued due to hallucinosis. Tolerance to this untoward effect was not observed.
There have been rare reports of pleuritis, pleural effusion, pleural fibrosis, pericarditis, pericardial effusion or retroperitoneal fibrosis in patients taking 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 other ergot derivatives. Patients with a history of such events should be carefully monitored clinically and with appropriate radiographic and laboratory studies while taking pergolide.
Precautions
Caution should be exercised when administering pergolide to patients prone to cardiac dysrhythmias or with significant underlying cardiac disease. In a placebo-controlled study, patients taking pergolide were found to have significantly more episodes of atrial premature contractions (APCs) and sinus tachycardia.
Use in patients on levodopa may cause or exacerbate dyskinesia, confusion and hallucinations. Abrupt discontinuation of pergolide may precipitate the onset of hallucinations and confusion. Pergolide should be discontinued gradually whenever possible even if the patient is to remain on levodopa.
No specific laboratory tests are essential for the management of patients on pergolide. Periodic routine evaluation for all patients is appropriate.
Information for Patients
Patients and their families should be informed of the common adverse consequences of the use of Permax ( see Adverse Effects) 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 breastfeeding an infant.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Two-year carcinogenicity studies in mice and rats used doses up to 340 and 12 times the maximum human oral dose (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. These occurrences are probably attributable to the high oestrogen/progesterone ratio, which would occur in rodents as a result of the prolactin-inhibiting action of pergolide. These endocrine mechanisms are not present in humans. There is no known correlation between uterine malignancies occurring in pergolide-treated rodents and human risk.
Mutagenic potential was evaluated in a battery of tests. A weak response was noted in one test, a mammalian cell-point-mutation assay, only after metabolic activation with rat liver microsomes, but the other five tests were negative. The relevance to humans is unknown.
Impaired fertility was observed in mice at the highest dose (5.6 mg/kg/day). This may be related to depressed prolactin levels.
Use During Pregnancy and Lactation
Pregnancy
In animal studies, there was no evidence of harm to the foetus 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 six pregnancies that resulted in congenital abnormalities (three major, three minor); a causal relationship has not been established. Pergolide should be used during pregnancy only if clearly needed.
Lactation
It is not known whether this medicine is excreted in human milk. The pharmacologic action of pergolide suggests that it may interfere with lactation. Because many medicines are excreted in human milk and because of the potential for serious adverse reactions to pergolide in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the medicine, taking into account the importance of the medicine to the mother.
Effects on Ability to Drive and Operate Machinery
Because pergolide may cause somnolence, patients should be cautioned about operating hazardous machinery including motor vehicles, while taking pergolide.
Adverse Effects
Nervous System
Confusion; Dizziness; Dyskinesia; Hallucinations; Insomnia; Somnolence
Gastrointestinal
Constipation; Diarrhoea; Nausea; Vomiting
Cardiovascular
Palpitation; Orthostatic hypotension; Syncope
Respiratory
Dyspnoea
Skin and Appendages
Rash
Other Uncommon or Rare Undesirable Effects
Fever; Liver function tests abnormal; Pericarditis; Pericardial effusion; Pleuritis; Pleural effusion; Pleural fibrosis; Retroperitoneal fibrosis; Neuroleptic malignant syndrome (with rapid de-titration of pergolide).
Interactions
Because pergolide is approximately 90% associated with plasma proteins, caution should be exercised if it is co-administered with other medicines known to affect protein binding.
Dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthines) or metoclopramide, ordinarily should not be administered concurrently with pergolide (a dopamine agonist); these agents may diminish the effectiveness of pergolide.
Overdose
There is no clinical experience with massive overdose. Symptoms and signs may include vomiting, hypotension, agitation, severe hallucinations, severe involuntary movements, tingling sensations, palpitations, and ventricular extrasystoles.
Treatment
Symptomatic supportive therapy and cardiac monitoring is recommended. Arterial blood pressure should be maintained. An antiarrhythmic agent may be necessary. If signs of CNS stimulation are present, a phenothiazine or butyrophenone neuroleptic agent may be indicated. Activated charcoal may be considered instead of or in addition to gastric emptying. There is no experience with dialysis or haemoperfusion and these are unlikely to be of benefit because pergolide is highly protein bound.
Pharmaceutical Precautions
Store below 25°C (77°F).
Shelf Life
Shelf life is 2 years.
Major Incompatibilities
None stated.
Package Quantities
Permax tablets are packed in cold-form aluminium blisters and are available in packs of 100 tablets.
Further Information
Permax is chemically designated as 8 - ß{(methylthio)methyl}-6-propylergoline monomethanesulphonate and has the empirical formula of C19H26N2S.CH4O3S. Its molecular weight is 410.59. The formula weight of the base is 314.5; 1 mg of base corresponds to 3.18 micromol.
Excipients
Permax tablets include the following inactive ingredients:
Permax tablet 0.05 mg
- lactose
- croscarmellose sodium
- povidone
- magnesium stearate
- l-methionine
- iron oxide yellow (E172)
Permax tablet 0.25 mg
- lactose
- croscarmellose sodium
- povidone
- magnesium stearate
- iron oxide yellow (E172)
- FD&C blue no.2 (E132)
Permax tablet 1.0 mg
- lactose
- croscarmellose sodium
- povidone
- magnesium stearate
- iron oxide red (E172)
