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 cabergoline, other ergot alkaloids or to any of the excipients.

History of pulmonary, pericardial and retroperitoneal fibrotic disorders.

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

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 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 creatine measurements can also be used to help in the diagnosis of fibrotic disorder.

Valvulopathy has been associated with cumulative doses, therefore patients should be treated with thelowest 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 ESR 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 (See Section 4.3).

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:

• Pleuropulmonary 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 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.

Cabergoline 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 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.

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, thus indicating that dose regimens in Parkinsonian patients with severe hepatic insufficiency should be modified accordingly.

In addition, by analogy with other ergot derivatives, Cabaser should be given with caution to patients suffering from severe cardiovascular disease, Raynaud's syndrome, peptic ulcer, gastrointestinal bleeding or a history of serious, particularly psychotic mental disease. Symptomatic hypotension can occur following adminstration of Cabaser: particular attention should be paid when administering Cabaser concomitantly with other drugs known to lower blood pressure.

Cabergoline has been associated with somnolence and episodes of sudden sleep onset, particularly in Patients with Parkinson's disease. Sudden onset of sleep during activities, in some cases without awareness or warning signs, has been reported uncommonly. 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. Furthermore a reduction of dosage or termination of therapy may be considered.

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

Pathological gambling, increased libido and hypersexuality have been reported in patients treated with dopamine agonists for Parkinson's disease, including Cabergoline/Cabaser.

No pharmacokinetic interaction with L-Dopa or selegiline was observed in the studies carried out in parkinsonian patients. The concomitant use of other drugs, particularly other antiparkinsonian non-dopamine-agonist agents, was not associated with detectable interactions modifying the efficacy and safety of Cabaser.

No other information is available about possible 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.

By analogy with other ergot derivatives, Cabaser should not be used in association with macrolide antibiotics (e.g erythromycin) since the systemic bioavailability of Cabaser and adverse effects could increase.

Cabaser has been shown to cross the placenta in rats: it is unknown whether this occurs also in humans.

Animal studies in rats and mice have not demonstrated any teratogenic effect or any effect of the compound on global reproductive performance. In clinical studies there have been over 100 pregnancies in women treated with cabergoline for hyperprolactinemic disorders. The compound was generally taken during the first 8 weeks after conception. Among the pregnancies evaluable so far, there were approximately 85% live births and about 10% spontaneous abortions. Three cases of congenital abnormalities (Down's syndrome, hydrocephalus, malformation of lower limbs) which led to therapeutic abortion and three cases of minor abnormalities in live births were observed.

These incidence rates are comparable with those quoted for normal populations and for women exposed to other ovulation-inducing drugs. Based on the above data, the use of the product does not appear to be associated with an increased risk of abortion, premature delivery, multiple pregnancy or congenital abnormalities.

Because clinical experience is still limited and the drug has a long half-life, as a precautionary measure it is recommended that women seeking pregnancy discontinue Cabaser one month before intended conception, in order to prevent possible foetal exposure to the drug. If conception occurs during therapy, treatment is to be discontinued as soon as pregnancy is confirmed, to limit foetal exposure to the drug.

In rats cabergoline and/or its metabolites are excreted in milk. Lactation is expected to be inhibited/suppressed by Cabaser, in view of its dopamine-agonist properties. Therefore, while no information on the excretion of cabergoline in maternal milk in humans is available, puerperal women should be advised not to breast-feed in case of failed lactation inhibition/suppression by the product.

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 (see also Section 4.4).

About 1070 parkinsonian patients have received Cabaser as adjuvant therapy to L-dopa in clinical studies; of these 74% had at least one adverse event, mainly of mild to moderate severity and transient in nature, and requiring discontinuation in a small proportion of cases.

In the majority of cases (51%), events were related to the nervous system: most frequently reported events were dyskinesia, hyperkinesia, hallucinations or confusion. The gastrointestinal system was involved in 33% of cases: events most frequently reported were nausea, vomiting, dyspepsia and gastritis. The cardiovascular system was involved in 27% of cases, most frequently reported events being dizziness and hypotension.

There have been reports of fibrotic and serosal inflammatory conditions, such as pleuritis, pleural effusion, pleural fibrosis, pulmonary fibrosis, pericarditis, pericardial effusion, cardiac valvulopathy and retroperitoneal fibrosis, in patients taking cabergoline (see 'Special warnings and special precautions for use'). The incidence of cardiac valvulopathy (including regurgitation) and related disorders (pericarditis and pericardial effusion) is considered to be very common.

There is limited information available on the reversibility of these reactions.

Other adverse events expected for the pharmacological class, in view of the vasoconstrictive properties, include angina (reported in about 1% of the patients on cabergoline) and erythromelalgia (observed in 0.4% of the patients). Similarly expected for the pharmacological class, peripheral oedema occurred in 6% of patients.

Gastric upset was more frequent in female than in male patients, while CNS events were more frequent in the elderly.

A blood pressure decrease of clinical relevance was observed mainly on standing in a minority of patients. The effect was mainly evident in the first weeks of therapy. Neither modification of heart rate nor consistent changes of ECG tracing were observed during Cabaser treatment.

Cabergoline is associated with somnolence and has been associated uncommonly with excessive daytime somnolence and sudden sleep onset episodes.

Alterations in standard laboratory tests are uncommon during long term therapy with Cabaser.

Patients treated with dopamine agonists for treatment of Parkinson's disease, including Cabergoline/Cabaser, 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.

The acute toxicity studies carried out in animals indicate very low toxicity, with a wide safety margin with respect to pharmacologically active doses. Clinical signs and cause of death, if any, were related to CNS stimulation.

There is no experience in humans of overdosage with Cabaser in the proposed indication: it is likely to lead to symptoms due to over-stimulation of dopamine receptors. These might include nausea, vomiting, gastric complaints, hypotension, confusion/psychosis or hallucinations. The vomiting stimulating properties of dopamine agonists are expected to favour removal of unabsorbed drug. Supportive measures should be directed to maintain blood pressure, if necessary. In addition, in case of pronounced central nervous system effects (hallucinations) 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

December 2008

Company Ref: CA9_2