Cabaser® Tablets 1 mg

Cabaser® Tablets 2 mg

Cabergoline INN 1 mg, 2 mg,

For excipients, see 6.1

Tablet

Cabaser 1 mg tablets are white, oval, 3.8 x 7.4mm and concave with one side scored and engraved '7' on the left and '01' on the right

Cabaser 2 mg tablets are white, oval, 5.1 x 10mm and concave with one side scored and engraved '7' on the left and '02' on the right

Treatment of Parkinson's disease

If treatment with a dopamine agonist is being considered, cabergoline is indicated as second line therapy in patients who are intolerant or fail treatment with a non-ergot compound, as monotherapy, or as adjunctive treatment to levodopa plus dopa-decarboxylase inhibitor, in the management of the signs and symptoms of Parkinson's disease.

Treatment should be initiated under specialist supervision. The benefit of continued treatment should be regularly reassessed taking into account the risk of fibrotic reactions and valvulopathy (see sections 4.3, 4.4 & 4.8)

The tablets are for oral administration.

Since the tolerability of dopaminergic agents is improved when administered with food, it is recommended that Cabaser be taken with meals.

Cabaser is intended for chronic, long term treatment.

Adults and elderly patients

As expected for dopamine agonists, dose response for both efficacy and side effects appears to be linked to individual sensitivity. Optimization of dose should be obtained through slow initial dose titration, from starting doses of 1 mg daily. The dosage of concurrent levodopa may be gradually decreased, while the dosage of Cabaser is increased, until the optimum balance is determined. In view of the long half-life of the compound, increments of the daily dose of 0.5-1 mg should be done at weekly (initial weeks) or bi-weekly intervals, up to optimal doses.

The recommended therapeutic dosage is 2 to 3 mg/day for patients with signs and symptoms of Parkinson's disease. Cabaser should be given as a single daily dose.

Use in children

The safety and efficacy of Cabaser have not been investigated in children as Parkinson's disease does not affect this population.

Hypersensitivity to Cabaser, any excipient of the product, or any ergot alkaloid.

History of pulmonary, pericardial and retroperitoneal fibrotic disorders.

For long-term treatment: Evidence of cardiac valvulopathy as determined by pre-treatment echocardiography.

(See section 4.4 Special warnings and precautions for use – Fibrosis and cardiac valvulopathy and possibly related clinical phenomena)

General:

As with other ergot derivatives, Cabaser 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.

Hepatic Insufficiency:

Lower doses of Cabaser 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 Cabaser, particularly during the first days of administration of Cabaser. Care should be exercised when administering Cabaser 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 5HT_2B receptor, such as Cabaser. In some cases, symptoms or manifestations of cardiac valvulopathy improved after discontinuation of Cabaser.

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 Cabaser has been reported to result in improvement of signs and symptoms. (See section 4.3 Contraindications)

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 Cabaser treatment for the patient should be reassessed to determine the suitability of continued treatment with Cabaser.

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 Cabaser treatment might worsen the underlying disease. If fibrotic valvular disease is detected, the patient should not be treated with Cabaser (See section 4.3 contraindications).

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 should 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.

Cabaser should be discontinued if an echocardiogram reveals new or worsened valvular regurgitation, valvular restriction or valve leaflet thickening. (See Section 4.3 Contraindications)

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:

Cabaser 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. (See section 4.7 Effects on ability to drive and use machines)

The effects of alcohol on overall tolerability of Cabaser are currently unknown.

Psychiatric:

Pathological gambling, increased libido, and hypersexuality have been reported in patients treated with dopamine agonists including Cabaser. This has been generally reversible upon reduction of the dose or treatment discontinuation.

The concomitant use of antiparkinson non-dopamine agonists (eg, selegiline, amantadine, biperiden, trihexyphenidyl) was allowed in clinical studies for patients receiving CABASER. In studies where the pharmacokinetic interactions of CABASER with L-dopa or selegiline were evaluated, no interactions were observed.

No information is available about interaction between Cabaser and other ergot alkaloids: therefore the concomitant use of these medications during long-term treatment with Cabaser is not recommended.

Since Cabaser exerts its therapeutic effect by direct stimulation of dopamine receptors, it should not be concurrently administered with drugs which have dopamine-antagonist activity (such as phenothiazines, butyrophenones, thioxanthenes, metoclopramide) since these might reduce the therapeutic effect of Cabaser.

As with other ergot derivatives, Cabaser should not be used in association with macrolide antibiotics (e.g. erythromycin) due to increased systemic bioavailability.

In a twelve year observational study on pregnancy outcomes following cabergoline therapy, information is available on 256 pregnancies. Seventeen of these 256 pregnancies (6.6%) eventuated in major congenital malformations or abortion. Information is available on 23/258 infants who had a total of 27 neonatal abnormalities, both major and minor. Musculoskeletal malformations were the most common neonatal abnormality (10), followed by cardio-pulmonary abnormalities (5). There is no information on perinatal disorders or long-term development of infants exposed to intra-uterine cabergoline. Based on recent published literature, the prevalence of major congenital malformations in the general population has been reported to be 6.9% or greater. Rates of congenital abnormality vary between different populations. It is not possible to accurately determine if there is an increased risk as no control group was included.

It is recommended that contraception is used whilst on treatment with Cabaser.

In rats, Cabaser and/or its metabolites are excreted in milk. No information is available on excretion in breast milk in humans; however, lactation is expected to be inhibited/suppressed by Cabaser, in view of its dopamine agonist properties. Mothers should be advised not to breast-feed while being treated with Cabaser.

Patients being treated with Cabaser 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 (see section 4.4 Special warnings and precautions for use – Somnolence/Sudden Sleep Onset).

The following undesirable effects have been observed and reported during treatment with Cabaser 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).

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.

Cabaser 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, Cabaser 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 Cabaser 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 Cabaser not linked to the therapeutic effect relate only to blood pressure decrease. The maximal hypotensive effect of Cabaser 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 Cabaser 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 Cabaser as D₂ dopamine receptor agonists "in vitro".

The low urinary excretion of unchanged Cabaser has been confirmed also in studies with non-radioactive product. The elimination half-life of Cabaser, estimated from urinary excretion rates, is long (63-68 hours in healthy volunteers, 79-115 hours in hyperprolactinemic patients).

The pharmacokinetics of Cabaser 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 Cabaser 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 Cabaser.

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.

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 Cabaser indicate a consistent safety margin for this compound in rodents and in monkeys, as well as a lack of teratogenic, genotoxic or carcinogenic potential.

Lactose anhydrous NF, USP

Leucine Ph Eur

Not applicable

24 months at room temperature (25^oC).

There are no special precautions for storage.

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.

Bottles of Cabaser are supplied with desiccant in the caps. This desiccant must not be removed.

Pharmacia Laboratories Limited

Ramsgate Road

Sandwich

Kent

CT13 9NJ

United Kingdom

1mg: PL 00022/0169

2mg: PL 00022/0170

14 February 1996

August 2010

Company Ref: CA10_0