When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.
Changes
3. PHARMACEUTICAL FORM
Deleted:
The scoreline is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
4. CLINICAL PARTICULARS
4.8 Undesirable effects
Added (bold)
Other events that have been reported include insomnia, confusion, dizziness, constipation, diarrhoea, abnormal liver function tests, postural hypotension, syncope, palpitation, atrial premature contractions, sinus tachycardia, peripheral vasospasm, rash, fever, Raynauds phenomenon and neuroleptic malignant syndrome (with rapid detitration of pergolide), blood creatine phosphokinase increased (in the absence of NMS). Hiccups and erythromelalgia (warm, red, painful swelling of the extremities) have also been reported.
6. PHARMACEUTICAL PARTICULARS
6.6 Special precautions for disposal and other handling
Deleted (strikethrough) Added:
No special requirements.Do not crush tablets. Caution is advised to minimize exposure risks when splitting tablets. In spontaneous cases, reports of eye irritation, irritating smell, or headache when pergolide tablets were split or crushed have been identified. In animal studies, pergolide was found to cause eye irritation and inhalation toxicity. In the event of pergolide powder exposure to the eye, the affected eye should be flushed immediately with water, and medical advice obtained. For nasal irritation, move to fresh air.
10. DATE OF REVISION OF THE TEXT
New date:
28 January 2010
4.2 Posology and method of administration
Added (bold) Deleted (strikethrough):
The useDoses of pergolide mesilate at doses above 5mg 3mg/day (5000 3000 micrograms/day) is not recommended are not to be used either as monotherapy or with levodopa due to the risk of fibrotic cardiac valvulopathy (see section 4.4) that might increase in frequency with greater daily doses and or cumulative exposure. However, valvulopathy and fibrotic reactions have been reported during treatment with pergolide at a variety of doses less than 3mg/day.
Adjunctive treatment
Added (bold):
The dosage may then be increased by 250 micrograms/day every third day until an optimal therapeutic dosage is achieved but not to exceed 3 mg/day.
Monotherapy
After day 30, the daily dose should be increased by at most 250 micrograms twice a week until an optimal therapeutic response is achieved but not to exceed 3 mg/day.
4.3 Contraindications
Anatomical evidence of cardiac valvulopathy of any valve (e.g. echocardiogram showing valve leaflet thickening, valve restriction, valve mixed restriction-stenosis).
Added:
Evidence of cardiac valvulopathy as determined by pre-treatment echocardiography.
4.4 Special warnings and precautions for use
The incidence of treatment emergent cardiac valvulopathy has not yet been determined although some studies have suggested that, in patients taking pergolide, asymptomatic cases of valvulopathy using echocardiography have been identified very commonly. Other studies have suggested that the background prevalence of asymptomatic valvulopathy is very common in the elderly population.
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 shouldmust undergo a cardiovascular evaluation,
There is some evidence that higher dose and/or cumulative exposure are risk factors for development of valvular pathology.
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.
Additional appropriate investigations such as erythrocyte sedimentation rate, chest X-ray and serum creatinine measurements should be performed if necessary to support a diagnosis of a fibrotic disorder. 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.
Clinical diagnostic monitoring for development of valvular disease or fibrosis, as appropriate, is recommendedessential. Following treatment initiation, the first echocardiogram shouldmust 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 shouldmust 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 (e.g. physical examination, carefulincluding cardiac auscultation, x-ray, echocardiogramCT 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.
Cardiac Disorders: Very common: cardiac valvulopathy (including regurgitation) and related disorders (pericarditis and pericardial effusion).
18 June 2009
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 50 microgram tablet contains 273.3mg of lactose as lactose monohydrate.
Each 250 microgram tablet contains 271.8mg of lactose as lactose monohydrate.
Each 1000 microgram tablet contains 272.1mg of lactose as lactose monohydrate.
Each 50 microgram tablet contains 287mg of lactose monohydrate per tablet.
Each 250 and 1000 microgram tablet contains 286mg of lactose monohydrate per tablet.
6.1 List of excipient(s)
Changed:
Methionine (50 microgram and 250 microgram tablets only)
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of last renewal of authorisation: 18 October 2008
04 January 2009
Amended Paragraph:
The use of pergolide mesilate at doses above 5mg/day (5000 micrograms/day) is not recommended either as monotherapy or with levodopa due to the risk of fibrotic cardiac valvulopathy (See section 4.4). Valvulopathy and fibrotic reactions have been reported during treatment with pergolide at a variety of doses less than 5mg/day, including during treatment with lower doses within the recommended dose range.
4.3 Special warnings and precautions for use
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.
Inserted:
Added bold text:
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 ‘Posology and method of administration’) 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 ‘Interactions with other medicinal products and other forms of interaction’).
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.
Other events that have been reported include insomnia, confusion, dizziness, constipation, diarrhoea, abnormal liver function tests, postural hypotension, syncope, palpitation, atrial premature contractions, sinus tachycardia, peripheral vasospasm, rash, fever, Raynauds phenomenon and neuroleptic malignant syndrome (with rapid detitration of pergolide), blood creatine phosphokinase increased (in the absence of NMS).
6.6 Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product
7. MARKETING AUTHORISATION HOLDER
Eli Lilly and Company Limited
Lilly House
Priestley Road
Basingstoke
Hampshire, RG24 9NL
England
November 2007
1. NAME OF THE MEDICINAL PRODUCT
Changed ‘Celance 1mg tablets’ to ‘Celance 1000 microgram tablets’.
Added (new text in bold):
Each tablet contains, as the active ingredient, pergolide mesilate equivalent to 50 micrograms of pergolide.
Each tablet contains, as the active ingredient, pergolide mesilate equivalent to 250 micrograms of pergolide.
Each tablet contains, as the active ingredient, pergolide mesilate equivalent to 1000 micrograms of pergolide.
Excipients:
Each 1000 microgram tablet contains 272.1mg of lactose as lactose monohydrate
Tablets (ivory, modified rectangle shaped, scored, marked ‘Lilly 4131’ containing 50 micrograms pergolide base.
Tablets (green, modified rectangle shaped, scored, marked ‘Lilly 4133’ containing 250 micrograms pergolide base.
Tablets (pink, modified rectangle shaped, scored, marked ‘Lilly 4135’ containing 1000 micrograms pergolide base.
Added (new text in bold and deletions in strikethrough text):
4.1 Therapeutic indications
If treatment with a dopamine agonist is being considered, pergolide mesilate is indicated as second line therapy in patients who are intolerant or fail treatment with a non-ergot dopamine agonist compound, as monotherapy, or as adjunctive treatment to levodopa in the management of the signs and symptoms of Parkinson’s disease.
New text in bold and deleted text in strikethrough:
Administration of pergolide mesilate should be initiated with a daily dosage of 50 micrograms for the first 2 days. The dosage should then be gradually increased by 100 or 150 micrograms/day every third day over the next 12 days of therapy. The dosage may then be increased by 250 micrograms/day every third day until an optimal therapeutic dosage is achieved.
Pergolide mesilate is usually administered in divided doses 3 times per day. During dosage titration, the dosage of concurrent l-dopa may be cautiously decreased.
In clinical studies, the mean therapeutic daily dosage of pergolide mesilate was 3mg/day (3000 micrograms/day). The average concurrent daily dosage of l-dopa/carbidopa (expressed as l-dopa) was approximately 650mg/day. The efficacy of pergolide mesilate at doses above 5mg/day (5000 micrograms/day) has not been systematically evaluated.
The following titration should be used for initiation of pergolide as monotherapy:
Day
Morning
Noon
Evening
Total Dosage
1
‑
50 micrograms
2‑4
100 micrograms
5‑7
200 micrograms
8‑10
300 micrograms
11‑13
150 micrograms
400 micrograms
14‑17
600 micrograms
18‑21
250 micrograms
750 micrograms
22‑24
500 micrograms
1000 micrograms
25‑27
1250 micrograms
28‑30
1500 micrograms
After day 30, the daily dose should be increased by at most 250 micrograms twice a week, until an optimal therapeutic response is achieved. Pergolide mesilate is usually administered in divided doses 3 times per day.
In clinical studies of pergolide as monotherapy, the mean dose was 2100 micrograms per day at 3 months and 2510 micrograms per day at 1 year of treatment.
Domperidone may be used at recommended doses at initiation of treatment to minimise any gastro‑intestinal symptoms experienced.
Added text in bold.
Therefore, during treatment attention should be paid to the signs and symptoms of:
Additional appropriate investigations such as erythrocyte sedimentation rate, chest x-ray and serum creatinine measurements should be performed if necessary to support a diagnosis of a fibrotic disorder. 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.
Additional appropriate investigations, such as erythrocyte sedimentation rate and serum creatinine measurements, should be performed at baseline and subsequently as appropriate.
Gastric ulcer has occurred in occasional Parkinsonian patients taking bromocriptine. There are reports of epigastric pain developing or worsening after therapy with pergolide. The possibility of ulceration should be borne in mind.
Patients and their families should be informed of the common adverse consequences of the use of pergolide mesilate and the risk of hypotension.
Added text in bold:
Hallucinations and Psychosis
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.
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.
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.
Pergolide should only be used under the regular supervision of an appropriate consultant having facilities for monitoring of response.
4.5 Interaction with other medicinal products and other forms of interaction
Pergolide mesilate potentiates the effects of levodopa, including the adverse effects, such as hypotension and dyskinesia.
The types of adverse events observed for pergolide as monotherapy, generally reflect those seen when pergolide is used as adjunctive treatment to levodopa (see below).
In clinical trials of pergolide as monotherapy, the overall reported incidence of nausea was higher than was reported in trials of pergolide as adjunctive therapy. Overall, only 3.2 percent of patients discontinued due to nausea or nausea and vomiting. However, the incidence of dyskinesia, hallucinations and dizziness was lower in monotherapy trials in comparison to trials of pergolide as adjunctive therapy.
Deleted text in strikethrough and new text in bold:
Digestive system: Nausea, vomiting, dyspepsia. occasionally reflecting peptic ulceration.
Other events that have been reported include insomnia, confusion, dizziness, constipation, diarrhoea, abnormal liver function tests, postural hypotension, syncope, palpitation, atrial premature contractions, sinus tachycardia, peripheral vasospasm, rash, fever, Raynaud’s phenomenon and compulsive self-rewarding behaviour (eg, pathological gambling), libido increased, and neuroleptic malignant syndrome (with rapid detitration of pergolide.
Pergolide is a novel drug substance. Any unusual or unexpected side-effects should be reported to the IMB.
Patients treated with dopamine agonists for treatment of Parkinson’s disease, including pergolide, especially at high doses, have been reported as exhibiting signs of pathological gambling, increased libido and hypersexuality, generally reversible upon reduction of the dose or treatment discontinuation.
5.2 Pharmacokinetic properties
Studies in male healthy volunteers have shown that pergolide appears to be active at the pituitary, as measured by attenuation of plasma prolactin levels, 2 hours post dosing. Suppression of prolactin following a dose of 50 micrograms may be complete and can last for at least 24 hours. In Parkinson’s disease patients, 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 2 hours post-dose.
Following oral administration of 14C radiolabelled pergolide mesilate to healthy subjects, approximately 55 percent of the administered radioactivity can be recovered as pergolide metabolites from the urine, 40 percent from the faeces and 5 percent from expired CO2, suggesting that a significant fraction is absorbed. Nothing can be concluded about the extent of presystemic clearance, if any.
5.3 Preclinical safety data
Furthermore, no increased risk of uterine There is no known correlation between malignancies has been identified among patients receiving pergolide. occurring in pergolide treated rodents and human risk.
6.1 List of excipients
Changes in bold:
L-Methionine (50 microgram and 250 microgram tablets only)
6.5 Nature and contents of container
Starter Pack (adjunctive treatment): 81 tablets containing 75 x 50 microgram tablets and 6 x 250 microgram tablets.
Starter Pack (monotherapy): 166 tablets containing 109 x 50 microgram tablets and 57 x 250 microgram tablets.
Not all pack sizes may be marketed
June 2007
For full list of excipients, see section 6.1.
Other events that have been reported include insomnia, confusion, dizziness, constipation, diarrhoea, abnormal liver function tests, postural hypotension, syncope, palpitation, atrial premature contractions, sinus tachycardia, peripheral vasospasm, rash, fever, Raynaud’s phenomenon, compulsive self-rewarding behaviour (eg, pathological gambling), libido increased, and neuroleptic malignant syndrome (with rapid detitration of pergolide).
11 May 2006