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Cabergoline 2mg Tablets

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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Cabergoline 2mg tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 2 mg cabergoline.

Excipient(s) with known effect: lactose 150.6 mg For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablet

The tablet can be divided into equal doses.

White, capsule-shaped, biconvex tablets with scores on both sides. One side is debossed with ‘CBG’ and ‘2’ on either side of the score.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

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 and 4.8).

4.2 Posology and method of administration

Posology

Adults and older people:

As expected for dopamine agonists, dose response for both efficacy and undesirable effects appears to be linked to individual sensitivity. Optimization of dose should be obtained through slow initial dose titration, from starting doses of 0.5mg cabergoline (de novo patients) and 1 mg cabergoline (patients on L dopa) daily. The dosage of concurrent levodopa may be gradually decreased, while the dosage of cabergoline 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 cabergoline should be done at weekly (initial weeks) or bi-weekly intervals, up to optimal doses.

The recommended therapeutic dosage is 2 to 3 mg cabergoline /day as adjuvant therapy to levodopa/carbidopa. The maximum dose of 3mg/day of cabergoline must not be exceeded. Cabergoline should be given as a single daily dose.

Paediatric population:

The safety and efficacy of cabergoline has not been investigated in children or adolescents as Parkinson’s disease does not affect this population.

Patients with hepatic or renal impairment

For patients with severe hepatic dysfunction or end stage renal failure see section 4.3 and 4.4.

Method of administration

Cabergoline is to be administered by the oral route. In order to reduce the risk of gastrointestinal undesirable effects it is recommended that cabergoline is taken with meals for all therapeutic indications.

4.3. Contraindications

Pre-eclampsia, eclampsia Uncontrolled hypertension.

Hypersensitivity to the active substance, any ergot alkaloid or to any excipient listed in section 6.1

History of pulomary, pericardial and retroperitoneal fibrotic disorders or adverse pulmonary reactions.

For long term treatment: evidence of cardiac valvulopathy of any valve 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).

4.4. Special warnings and precautions for use

General

As with other ergot derivatives, cabergoline should be given with caution to subjects with severe cardiovascular disease, hypotension, Raynaud's syndrome, peptic ulcer or gastrointestinal bleeding, or with a history of serious, particularly psychotic, mental disorders.

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

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 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 creatine 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.

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

Before initiating long-term treatment:

All patients should 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. (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:

•    Pleuropulmonary disease, such as dyspnoea, shortness of breath, persistent cough, or chest pain.

•    Renal insufficiency or ureteral/abdominal vascular obstructions 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 fibrotic disease 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 a 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 Contraindications).

The need for other clinical monitoring (e.g. physical examination including careful 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 fibrotic disorder.

Somnolence/sudden sleep onset:

Cabergoline has been associated with somnolence and episodes of sudden sleep onsetin patients with Parkinson's disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported. A reduction of dosage or termination of therapy may be considered (See section 4.7 Effects on ability to drive and use machines).

Psychiatric:

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 cabergoline. Dose reduction/tapered discontinuation should be considered if such symptoms develop.

Renal insufficiency:

No overall differences in the pharmacokinetics of cabergoline were observed in moderate to severe renal disease. The pharmacokinetics of cabergoline has not been studied in patients having end-stage renal failure, or in patients on haemodialysis; these patients should be treated with caution.

4.5 Interaction with other medicinal products and other forms of interaction

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

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

Concomitant use not recommended:

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

Precautions:

Interactions with other medicinal products that reduce blood pressure should be taken into consideration.

No pharmacokinetic interactions with L-dopa or selegiline have been observed in studies of patients with Parkinson’s disease. Pharmacokinetic interactions with other medicinal products cannot be predicted based on available information about the metabolism of cabergoline.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate and well-controlled studies from the use of cabergoline in pregnant women. Animal studies have not demonstrated teratogenic effects, but reduced fertility and embryo-toxicity were observed in association with pharmacodynamic activity (see section 5.3).

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 abormality (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.

Cabergoline should only be used during pregnancy if clearly indicated and after an accurate benefit/risk evaluation. (See section “Special warning and precautions for use” - Treatment of Hyperprolactinemic Disorders)

Due to the long half-life of the drug and limited data on in utero exposure, women planning to become pregnant should discontinue cabergoline one month before intended conception. If conception occurs during therapy, treatment should be discontinued as soon as pregnancy is confirmed to limit foetal exposure to the drug. Contraception should be continued for at least 4 weeks after stopping cabergoline.

Breast-feeding

In rats, cabergoline and/or its metabolites are excreted in milk. No information is available on the excretion in breast milk in humans; however, mothers should be advised not to breast-feed in case of failed lactation inhibition/suppression by cabergoline. Since it prevents lactation, cabergoline should not be administered to mothers with hyperprolactinemic disorders who wish to breast-feed their infants.

Fertility

Cabergoline restores ovulation and fertility in women with hyperprolactinaemic hypogonadism: since pregnancy might occur prior to reinitiation of menses, pregnancy testing is recommended as appropriate during the amenorrhoeic period and, once menses are reinitiated, every time a menstrual period is delayed by more than three days. Women not seeking pregnancy should be advised to use effective nonhormonal contraception during treatment and after cabergoline withdrawal. Because of limited experience on the safety of foetal exposure to cabergoline, it is advisable that women seeking pregnancy conceive at least one month after cabergoline discontinuation. As a precautionary measure, women who become pregnant should be monitored to detect signs of pituitary enlargement since expansion of pre-existing pituitary tumours may occur during gestation.

4.7 Effects on ability to drive and use machines

Patients should be careful when performing actions which require fast and accurate reaction during treatment initiation.

Patients treated with cabergoline and presenting with somnolence and/or sudden sleep 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 (eg, operating machines) until such episodes and somnolence have resolved (See section 4.4 Special warnings and precautions for use - Somnolence/sudden sleep onset).

4.8 Undesirable effects

The undesirable effects are usually dose-dependent, and can be reduced by decreasing the dose gradually.

Inhibition of lactation: Approximately 14% of the patients experience undesirable effects. The most common are low blood pressure (12%), dizziness (6%) and headaches (5%). Long-term treatment increases the frequency of undesirable effects to approximately 70%.

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)

Uncommon

Palpitations

Not Known

Angina pectoris

Respiratory, thoracic and mediastinal disorders

Uncommon

Dyspnoea, pleural effusion, fibrosis, (including pulmonary fibrosis), epistaxis

Very rare

Pleural fibrosis

Not Known

Respiratory disorder, respiratory failure, pleuritis, chest pain

Immune system disorders

Uncommon

Hypersensitivity reaction

Nervous system disorders

Very common

Headache*, dizziness/vertigo*

Common

Somnolence

Uncommon

Transient hemianopsia, syncope,

Not Known

Sudden sleep onset, tremor,

Eye disorders

Not Known

Visual impairment

Psychiatric disorders

Common

Depression

MedDRA System Organ Class

Frequency

Undesirable Effects

Uncommon

Increased libido

Not Known

Aggression, delusions, hypersexuality, pathological gambling, psychotic disorder, hallucinations

Vascular disorders

Common

Cabergoline generally exerts a hypotensive effect in patients on long-term treatment; Postural hypotension, hot flushes**

Uncommon

Digital vasospasm, fainting

Gastrointestinal

disorders

Very common

Nausea*, dyspepsia, gastritis, abdominal

Common

Constipation, vomiting**

Rare

Epigastric pain

General disorders and administration site conditions

Very Common

Asthenia***, fatigue

Uncommon

Oedema, peripheral oedema

Hepato-biliary

Not Known

Hepatic function abnormal

Skin and

subcutaneous tissue disorders

Common

Facial redness

Uncommon

Rash, alopecia

Musculoskeletal and connective tissue

Uncommon

Leg cramps

Rare

Cramp in fingers

Reproductive system and breast disorders

Common

Breast pain

MedDRA System Organ Class

Frequency

Undesirable Effects

Investigations

Common

Asymptomatic decreases in blood pressure (> 20 mmHg systolic and > 10 mmHg

Uncommon

A decrease in haemoglobin values have been observed in amenhorrheic women during the first few months after menses

Not Known

Blood creatinine phosphokinase increased, liver function tests abnormal

*Very common in patients treated for hyperprolactinaemin disorders; Common in patients treated for inhibition/supression of lactation

** Common in patients treated for hyperprolactinaemic disorders; Uncommon in patients treated for inhibition/supression of lactation

*** Very common in patients treated for hyperprolactinaemic disorders; Uncommon in patients treated for inhibition/supression of lactation

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 cabergoline (see section „Special warnings and precautions for use“).

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.

4.9 Overdose

Symptoms of overdose would likely be those of over-stimulation of dopamine receptors, eg, 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Dopamine agonist

ATC code: N04BC06

Cabergoline is a synthetic ergot alkaloid and an ergoline derivate with long-acting dopamine agonist and prolactin-inhibiting properties. A central dopaminergic effect via D2-

receptor stimulation is achieved through higher doses than doses that reduce the levels of serum prolactin.

Controlled clinical studies have demonstrated that cabergoline is effective at an average dose of 4 mg/day following titration (up to 5-6 mg cabergoline/day in the different studies). Cabergoline reduces daily fluctuations in the motor function in patients with Parkinson’s disease that are being treated with levodopa/carbidopa. In newly diagnosed patients, cabergoline administered as monotherapy has been shown to produce somewhat less frequent clinical improvement compared with levodopa/carbidopa.

With regard to the endocrine effects of Cabergoline not related to the antiprolactinaemic effect, available data from humans confirm the experimental findings in animals indicating that the test compound is endowed with a very selective action with no effect on basal secretion of other pituitary hormones or cortisol.

The pharmacodynamic actions of cabergoline not correlated with the therapeutic effect only relate to blood pressure decrease. The maximal hypotensive effect of cabergoline as single dose usually occurs during the first 6 hours after active substance intake and is dose-dependent both in terms of maximal decrease and frequency.

5.2 Pharmacokinetic properties

Absorption

After oral administration cabergoline is rapidly absorbed from the gastrointestinal tract as the peak plasma concentration is received within 0.5 to 4 hours.

Food does not appear to affect absorption and disposition of cabergoline. Distribution

“In-vitro” experiments showed that cabergoline at concentrations of 0.1 - 10 ng/ml is 41-42% bound to plasma proteins.

Biotransformation

In urine, the main metabolite identified is 6-allyl-8B-carboxy-ergoline, which accounts for 46% of the dose. Three additional metabolites are identified in urine, which account overall for less than 3% of the dose. The metabolites have been found to be much less potent than cabergoline in inhibiting prolactin secretion “in-vitro”.

Elimination

The elimination half-life of cabergoline, is long; (63-68 hours in healthy volunteers and 79115 hours in hyperprolactinaemic patients.

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)-for 0.5mg cabergoline dose.

Ten days after administration about 18% and 72% of the dose is recovered in urine and faeces, respectively. Unchanged cabergoline in urine accounts for 2-3% of the dose.

Linearitv/Non-linearitv

The pharmacokinetic profile is linear up to 7 mg per day.

5.3 Preclinical safety data

There were maternotoxic effects but no teratogenic effects in mice given cabergoline at doses up to 8 mg/kg/day (approximately 55 times the maximum recommended human dose) during the period of organogenesis.

A dose of 0.012 mg/kg/day (approximately 1/7 the maximum recommended human dose) during the period of organogenesis in rats caused an increase in postimplantation embryofetal losses. These losses could be due to the prolactin inhibitory properties of cabergoline in rats. At daily doses of 0.5 mg/kg/day (approximately 19 times the maximum recommended human dose) during the period of organogenesis in the rabbit, cabergoline caused maternotoxicity characterized by a loss of body weight and decreased food consumption. Doses of 4 mg/kg/day (approximately 150 times the maximum recommended human dose) during the period of organogenesis in the rabbit caused an increased occurrence of various malformations. However, in another study in rabbits, no treatment-related malformations or embryofetotoxicity were observed at doses up to 8 mg/kg/day (approximately 300 times the maximum recommended human dose).

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Anhydrous lactose L-Leucine

Magnesium stearate (E572)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Do not store above 30°C. Store in the original package in order to protect from moisture. The drying capsule or bag with silica gel must not be removed from the bottle.

6.5 Nature and contents of container

Brown glass bottles (type III) containing a dessication capsule with silica gel with an induction-sealed childproof aluminium membrane and childproof HDPE top.

Or

Brown glass bottles (type III) containing a dessication bag with silica gel with an induction-sealed childproof aluminium membrane and childproof PP top.

External box.

Packaging sizes: 2, 8, 14, 15, 16, 20, 28, 30, 32, 40, 48, 50, 60, 90, 98, 100 tablets. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirement.

7 MARKETING AUTHORISATION HOLDER

Teva UK Ltd.

East Sussex BN22 9AG United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 00289/0990

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

05/10/13

10 DATE OF REVISION OF THE TEXT

30/06/2014