Symptoms of overdose would likely be those of over-stimulation of dopamine receptors, e.g. nausea, vomiting, gastric complaints, postural hypotension, confusion/psychosis or hallucinations.
Supportive measures should be taken to remove unabsorbed drug and maintain blood pressure, if necessary. In addition, the administration of dopamine antagonist drugs may be advisable.
2 years
Not applicable
Lactose anhydrous
Leucine
The following undesirable effects have been observed and reported during treatment with cabergoline with the following frequencies: Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to ≤1/100); rare (>1/10,000 to ≤1/1,000); very rare (≤1/10,000), not known (cannot be estimated from the available data).
| MedDRA System Organ Class | Frequency | Undesirable Effects |
| Cardiac disorders | Very Common | Valvulopathy (including regurgitation) and related disorders (pericarditis and pericardial effusion) |
| Common* | Angina pectoris | |
| Respiratory, thoracic and mediastinal disorders | Common | Dyspnea |
| Uncommon | Pleural effusion, pulmonary fibrosis | |
| Very rare | Fibrosis ( including pleural fibrosis) | |
| Not Known | Respiratory disorder, respiratory failure, pleuritis, chest pain | |
| Immune system disorders | Uncommon | Hypersensitivity reaction |
| Nervous system disorders | Common | Headache, somnolence, dizziness/vertigo, dyskinesia |
| Uncommon | Hyperkinesia | |
| Not Known | Sudden sleep onset, syncope, tremor | |
| Eye disorders | Not Known | Visual impairment |
| Psychiatric disorders | Common | Hallucinations, sleep disturbances, increased libido, confusion |
| Uncommon | Delusions, psychotic disorder | |
| Not Known | Aggression, hypersexuality, pathological gambling | |
| Vascular disorders | Common | Cabergoline generally exerts a hypotensive effect in patients on long-term treatment; Postural hypotension |
| Uncommon | Erythromelalgia | |
| Not Known | Digital vasospasm | |
| Gastrointestinal disorders | Very common | Nausea |
| Common | Constipation, dyspepsia, gastritis, vomiting | |
| General disorders and administration site conditions | Very common | Peripheral oedema |
| Common | Asthenia | |
| Uncommon | Oedema, fatigue | |
| Hepato-biliary disorders | Uncommon | Hepatic function abnormal |
| Skin and subcutaneous tissue disorders | Uncommon | Rash |
| Not Known | Alopecia | |
| Musculoskeletal and connective tissue disorders | Not Known | Leg cramps |
| Investigations | Common | Liver function tests abnormal, decreased haemoglobin, haematocrit, and/or red blood cell (>15% vs baseline) |
| Not Known | Blood creatinine phosphokinase increased |
* When concomitant use with levodopa therapy
Impulse control disorders
Pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists including Cabaser.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
Almost all the findings noted throughout the series of preclinical safety studies are a consequence of the central dopaminergic effects or the long-lasting inhibition of PRL in rodents with a specific hormonal physiology different to man.
Preclinical safety studies of cabergoline indicate a consistent safety margin for this compound in rodents and in monkeys, as well as a lack of teratogenic, genotoxic or carcinogenic potential.
Pharmacotherapeutic group: Dopamine agonists, ATC code: N04BC06
Cabergoline is a dopaminergic ergoline derivative endowed with potent and long-lasting dopamine D2 receptor agonist properties. In rats the compound, acting at D2 dopamine receptors on pituitary lactotrophic cells, decreases PRL secretion at oral doses of 3-25 mcg/kg, and in vitro at a concentration of 45 pg/ml. In addition, cabergoline exerts a central dopaminergic effect via D2 receptor stimulation at doses higher than those effective in lowering serum PRL levels. Improvement of motor deficit in animal models of Parkinson's disease was present at oral daily doses of 1-2.5 mg/kg in rats and at s.c. doses of 0.5-1 mg/kg in monkeys.
In healthy volunteers the administration of cabergoline at single oral doses of 0.3-2.5 mg was associated with a significant decrease in serum PRL levels. The effect is prompt (within 3 hours of administration) and persistent (up to 7-28 days). The PRL-lowering effect is dose-related both in terms of degree of effect and duration of action.
The pharmacodynamic actions of cabergoline not linked to the therapeutic effect relate only to blood pressure decrease. The maximal hypotensive effect of cabergoline as a single dose usually occurs during the first 6 hours after drug intake and is dose-dependent both in terms of maximal decrease and frequency.
The pharmacokinetic and metabolic profiles of cabergoline have been studied in healthy volunteers of both sexes, in female hyperprolactinemic patients and in parkinsonian patients. After oral administration of the labelled compound, radioactivity was rapidly absorbed from the gastrointestinal tract as the peak of radioactivity in plasma was between 0.5 and 4 hours. Ten days after administration about 18/20% and 55/72% of the radioactive dose (3H-cabergoline/14C-cabergoline) was recovered in urine and faeces, respectively. Unchanged drug in urine accounted for 2-3% of the dose.
In urine, the main metabolite identified was 6-allyl-8b-carboxy-ergoline, which accounted for 4-6% of the dose. Three additional metabolites were identified in urine, which accounted overall for less than 3% of the dose. The metabolites have been found to be much less potent than cabergoline as D2 dopamine receptor agonists "in vitro".
The low urinary excretion of unchanged cabergoline has been confirmed also in studies with non-radioactive product. The elimination half-life of cabergoline, estimated from urinary excretion rates, is long (63-68 hours in healthy volunteers, 79-115 hours in hyperprolactinemic patients).
The pharmacokinetics of cabergoline seem to be dose-independent both in healthy volunteers (doses of 0.5-1.5 mg) and parkinsonian patients (steady state of daily doses up to 7 mg/day).
On the basis of the elimination half-life, steady state conditions should be achieved after 4 weeks, as confirmed by the mean peak plasma levels of cabergoline obtained after a single dose (37+8 pg/ml) and after a 4 week multiple-regimen (101+43 pg/ml). "In vitro" experiments showed that the drug at concentrations of 0.1-10 ng/ml is 41-42% bound to plasma proteins.
Food does not appear to affect absorption and disposition of cabergoline.
While renal insufficiency has been shown not to modify cabergoline kinetics, hepatic insufficiency of severe degree (> 10 Child-Pugh score, maximum score 12) has been shown to be associated with an increase of AUC.
01/2014
Pfizer Limited
Ramsgate Road
Sandwich
Kent
CT13 9NJ
Do not store above 25 °C
The tablets are contained in Type I amber glass bottles with tamper resistant screw caps which contain silica gel desiccant.
Each bottle contains 20 or 30 tablets and is enclosed in an outer cardboard carton.
Not all pack sizes may be marketed.
PL 00057/0936
General:
As with other ergot derivatives, cabergoline should be given with caution to patients with severe cardiovascular disease, Raynaud's syndrome, peptic ulcer or gastrointestinal bleeding, or with a history of serious, particularly psychotic, mental disorders.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
The effects of alcohol on overall tolerability of cabergoline are currently unknown.
Hepatic Insufficiency:
Lower doses of cabergoline should be considered in patients with severe hepatic insufficiency. Compared to normal volunteers and those with lesser degrees of hepatic insufficiency, an increase in AUC has been seen in patients with severe hepatic insufficiency (Child-Pugh Class C) who received a single 1 mg dose.
Postural Hypotension:
Postural hypotension can occur following administration of cabergoline, particularly during the first days of administration of cabergoline. Care should be exercised when administering cabergoline concomitantly with other drugs known to lower blood pressure.
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 cabergoline. In some cases, symptoms or manifestations of cardiac valvulopathy improved after discontinuation of cabergoline.
Erythrocyte sedimentation rate (ESR) has been found to be abnormally increased in association with pleural effusion/fibrosis. Chest x-ray examination is recommended in cases of unexplained ESR increases to abnormal values.
Serum creatinine measurements can also be used to help in the diagnosis of fibrotic disorder. Following diagnosis of pleural effusion/pulmonary fibrosis or valvulopathy, the discontinuance of cabergoline has been reported to result in improvement of signs and symptoms.
Valvulopathy has been associated with cumulative doses, therefore patients should be treated with the lowest effective dose. At each visit, the risk benefit profile of cabergoline treatment for the patient should be reassessed to determine the suitability of continued treatment with cabergoline.
Before initiating long-term treatment:
All patients must undergo a cardiovascular evaluation, including echocardiogram, to assess the potential presence of asymptomatic valvular disease. 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.
In patients with valvular regurgitation, it is not known whether cabergoline treatment might worsen the underlying disease. If fibrotic valvular disease is detected, the patient should not be treated with cabergoline.
During long-term 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 fibrotic disorders, 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.
Cabergoline should be discontinued if an echocardiogram reveals new or worsened valvular regurgitation, valvular restriction, valve leaflet thickening or fibrotic valvular disease.
The need for other clinical monitoring (e.g. 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.
Somnolence/Sudden Sleep Onset:
Cabergoline has been associated with somnolence and episodes of sudden sleep onset in patients with Parkinson's disease. Sudden onset of sleep during activities, in some cases without awareness or warning signs, has been reported. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with cabergoline. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. A reduction of dosage or termination of therapy may be considered.
Impulse control disorders:
Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioural symptoms of impulse control disorders including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists including Cabaser. Dose reduction/tapered discontinuation should be considered if such symptoms develop.
Patients should be careful when performing actions which require fast and accurate reaction during treatment initiation.
Patients being treated with cabergoline and presenting with somnolence and/or sudden sleep onset episodes must be informed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until such episodes and somnolence have resolved.
Bottles of Cabaser are supplied with desiccant in the caps. This desiccant must not be removed.
14 February 1996
