| Fibrosis and Cardiac Valvulopathy and possibly related clinical phenomena Fibrotic and serosal inflammatory disorders, such as pleuritis, pleural effusion, pleural fibrosis, pulmonary fibrosis, pericarditis, pericardial effusion, cardiac valvulopathy involving one or more valves (aortic, mitral and tricuspid), or retroperitoneal fibrosis, have occurred after prolonged usage of ergot derivatives with agonist activity at the serotonin 5HT2B receptor, such as pergolide. In some cases, symptoms or manifestations of cardiac valvulopathy improved after discontinuation of pergolide.There is evidence that higher dose and/or cumulative exposure are risk factors for development of valvular pathology. However, valvulopathy and fibrotic reactions have been reported during treatment with pergolide at doses less than 0.5 mg/day.Before initiating treatment: All patients must undergo a cardiovascular evaluation, including echocardiogram, to assess the potential presence of asymptomatic valvular disease. In patients with valvular regurgitation, it is not known whether pergolide treatment might worsen the underlying disease. If fibrotic valvular disease is detected, the patient should not be treated with pergolide (see section 4.3).It is also appropriate to perform baseline investigations of erythrocyte sedimentation rate or other inflammatory markers, lung function/chest X-ray and renal function prior to initiation of therapy.During treatment: Fibrotic disorders can have an insidious onset and patients should be regularly monitored for possible manifestations of progressive fibrosis.Therefore, during treatment attention should be paid to the signs and symptoms of:• Pleuro-pulmonary disease, such as dyspnoea, shortness of breath, persistent cough or chest pain.• Renal insufficiency or ureteral/abdominal vascular obstruction that may occur with pain in the loin/flank and lower limb oedema, as well as any possible abdominal masses or tenderness that may indicate retroperitoneal fibrosis.• Cardiac failure; cases of valvular and pericardial fibrosis have often manifested as cardiac failure. Therefore, valvular fibrosis (and constrictive pericarditis) should be excluded if such symptoms occur.Clinical diagnostic monitoring for development of valvular disease or fibrosis, as appropriate, is essential. Following treatment initiation, the first echocardiogram must occur within 3-6 months, thereafter, the frequency of echocardiographic monitoring should be determined by appropriate individual clinical assessment, with particular emphasis on the above-mentioned signs and symptoms, but must occur at least every 6 to 12 months.Pergolide should be discontinued if an echocardiogram reveals new or worsened valvular regurgitation, valvular restriction or valve leaflet thickening (see section 4.3). The need for other clinical monitoring (eg, physical examination, including cardiac auscultation, x-ray, CT scan) should be determined on an individual basis.Additional appropriate investigations such as erythrocyte sedimentation rate and serum creatinine measurements should be performed if necessary to support a diagnosis of a fibrotic disorder. Endocrine Effects 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 antiparkinson therapy, including pergolide.Hypotension Patients and their families should be informed of the common adverse consequences of the use of pergolide mesilate and the risk of hypotension. Patients should be warned to begin therapy with low doses and to increase dosage in carefully adjusted increments over a period of 3 to 4 weeks (see section 4.2) to minimise the risk of symptomatic orthostatic or postural hypotension and/or sustained hypotension. With gradual dosage titration, tolerance to the hypotension usually develops (but see section 4.5).Hallucinations and Psychosis and related events Hallucinations are known to be associated with dopamine agonists and levodopa treatment. In controlled trials, pergolide mesilate with l-dopa caused hallucinosis in about 14 percent of patients, as opposed to 3 percent taking placebo with l-dopa. This was of sufficient severity to cause discontinuation of treatment in about 3 percent of those enrolled. Tolerance to this untoward effect was not observed. Pergolide should only be administered with caution in patients with a history of psychosis, since pre-existing states of confusion and hallucination may be exacerbated.Study findings in the Elderly In the placebo-controlled trial, 2 of 187 patients treated with placebo died, as compared with 1 of 189 patients treated with pergolide mesilate. Of the 2,299 patients treated with pergolide mesilate in pre-marketing studies evaluated in October 1988, 6.2 percent died while on the drug or shortly after discontinuation. The patient population under evaluation was elderly, ill and at high risk for death. A case-by-case review 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 these deaths.Cardiac Disease/Arrhythmia 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 mesilate had significantly more episodes of atrial premature contractions (APCs) and sinus tachycardia.Somnolence Pergolide has been associated with somnolence and episodes of sudden sleep onset, particularly in patients with Parkinson's disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported rarely. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with pergolide.Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore, a reduction of dosage or termination of therapy may be considered.Patients should be advised to tell their doctor if they become pregnant or intend to become pregnant during therapy. They should also tell their doctor if they are breast-feeding.Pathological gambling, increased libido and hypersexuality Pathological gambling, increased libido and hypersexuality have been reported in patients treated with dopamine agonists for Parkinson's disease, including pergolide.Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. | |