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Produktinformationen för Cabergoline ratiopharm 0,5 mg tablett, MTnr 23663, gäller vid det tillfälle då läkemedlet godkändes. Informationen kommer inte att uppdateras eftersom läkemedlet inte marknadsförs i Sverige. Av samma anledning finns inte någon svensk produktinformation.

Den engelska produktinformationen kommer dock att uppdateras för de produkter där Sverige är referensland.

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Cabergoline ratiopharm 0.5 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 0.5 mg cabergoline.

Excipient: lactose 75.8 mg

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet

White, oval, flat tablets with bevelled edges. One side is smooth and the other side has a dividing score line and is debossed with ‘CBG’ and ‘0.5’ on either side of the score.

The tablet can be divided into equal halves.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Inhibition of lactation for medical reasons.

Hyperprolactimaemic disorders

Prolactin secreting pituitary adenomas

Idiopathic hyperprolactinaemia

It is recommended that the medicinal product is initially prescribed by an appropriate specialist or after consulting a specialist.

4.2 Posology and 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.

Adults:

Treatment of hyperprolactinaemic disorders:

The recommended initial dosage is 0.5 mg cabergoline per week given in one or two doses (e.g. on Monday and Thursday) per week. The weekly dose should be increased gradually, preferably by adding 0.5 mg cabergoline per week at monthly intervals until an optimal therapeutic response is achieved.

The therapeutic dosage is usually 1 mg cabergoline per week and ranges from 0.25 mg to 2 mg cabergoline per week. Doses of up to 4.5 mg cabergoline per week have been used in hyperprolactinaemic patients. The maximum daily dose is 3 mg.

The weekly dose may be given as a single administration or divided into two or more doses per week according to patient tolerability. Division of the weekly dose into multiple administrations is advised when doses higher than 1 mg cabergoline per week are to be given since the tolerability of doses greater than 1 mg cabergoline taken as a single weekly dose has been evaluated only in a few patients.

Patients should be evaluated during dose escalation to determine the lowest dosage that produces the therapeutic response.

For inhibition of lactation:

Cabergoline should be administered within the first 24 hourspost-partum. The recommended therapeutic dosage is 1 mg cabergoline given as a single dose. A single dose of 0.25 mg of cabergoline should not be exceeded in nursing women treated for suppression of established lactation to avoid potential postural hypotension.

Use in patients with hepatic or renal dysfunction.

Use in patients with hepatic insufficiency and renal insufficiency see sections 4.3 and 4.4

Use in children and adolescents:

The safety and efficacy of cabergoline has not been established in subjects less than 16 years of age.

Use in the elderly:

As a consequence of the indications for which cabergoline is presently proposed, the experience in elderly is very limited. Available data do not indicate a special risk.

4.3 Contraindications

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

• History of pulmonary, pericardial and retroperitoneal fibrotic disorders.

• Pre-eclampsia, eclampsia

• Post-partum hypertension or uncontrolled hypertension.

• Severe impairment of liver function

• History of psychosis or risk of post-partum psychosis

• For long-term treatment: Evidence of cardiac valvulopathy as determined by pre-treatment echocardiography (see section 4.4).

4.4 Special warnings and precautions for use

General:

As with other ergot derivatives, cabergoline should be given with caution to patients with severecardiovascular disease, 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.

Postural Hypotension:

Postural hypotension can occur following 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, percadial 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 activityat the serotonin 5-HT2B receptor, such as cabergoline. In some cases, symtoms 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.

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 functions/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:

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 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-ra, CT scan) should be determined on an individual basis.

Additional appropriate investigations such as eryththrocyte 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 . Dopamine agonists can be associated withsudden sleep onsetepisodes, in patients with Parkinson’s disease. 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 during treatment with cabergoline (see section 4.7). A reduction in dosage or termination of treatment may be considered (see section 4.7).

Inhibition/Suppression of Physiologic Lactation:

As with other ergot derivatives, cabergoline should not be used in women with pregnancy-induced hypertension, for example, preeclampsia or post-partum hypertension, unless the potential benefit is judged to outweigh the possible risk.

A single dose of 0.25 mg of cabergoline should not be exceeded in nursing women treated for suppression of established lactation to avoid potential postural hypotension. (See section 4.2).

Treatment of Hyperprolactinemic Disorders:

Because hyperprolactinemia accompanied with amenorrhoea/galactorrhoea and infertility may be associated with pituitary tumour, a complete evaluation of the pituitary is indicated before treatment with cabergoline is initiated.

Monitoring of serum prolactin levels at monthly intervals is advised since, once the effective therapeutic dosage regimen has been reached, serum prolactin normalisation is usually observed within two to four weeks.

After cabergoline withdrawal, recurrence of hyperprolactinaemia is usually observed. However, persistent suppression of prolactin levels has been observed for several months in some patients.

Cabergoline restores ovulation and fertility in women with hyperprolactinemic hypogonadism. Before administration of cabergoline, pregnancy should be excluded. Because clinical experience is still limited and the product has a long half-life, as a precautionary measure it is recommended that once regular ovulatory cycles have been achieved women seeking pregnancy discontinue cabergoline one month before intended conception.

Because pregnancy might occur prior to reinitiation of menses, a pregnancy test is recommended at least every 4 weeks during the amenorrheic period and, once menses are reinitiated, every time a menstrual period is delayed by more than 3 days. Women who wish to avoid pregnancy should be advised to use mechanical contraception during treatment with cabergoline and after discontinuation of cabergoline until recurrence of anovulation. As a precautionary measure, women who become pregnant should be monitored to detect signs of pituitary enlargement since expansion of pre-existing pituitary tumors may occur during gestation.

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.

Cerebrospinal fluid leakage

Rhinorrhea of cerebrospinal fluid has occurred in some patients who were given cabergoline in the treatment of prolactin-producing adenomas. The mechanism causing such liquorrhea has not yet been fully elucidated. Most probably, a fistula in the skull base is released due to shrinkage of the dopamine agonist-sensitive tumour, through which the fluid is able to flow. Patients in whom the fistula is not sealed are at risk of developing meningitis.

Psychiatric:

Pathologic gambling, increased libido and hypersexuality have been reported in patients treated with dopamine agonists for Parkinson’s disease, including cabergoline.This has been generally reversible upon reduction of the dose or treatment discontinuation.

Other

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interactions with other medicinal products and other forms of interactions

No information is available about possible interactions 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 therapeutic effect of cabergoline.

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

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.

4.6 Pregnancy and lactation

Pregnancy

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 isno information on perinatal disordersor long-termdevelopment 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 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.

Before cabergolineadministration, pregnancy should be excluded and after treatment pregnancy should be prevented for at least one month. As cabergoline has an elimination half-life of 79-115 hours in hyperprolactinaemic patients, once regular ovulatory cycles have been achieved women seeking pregnancy should discontinue cabergolineone month before intended conception. This will prevent possible foetal exposure to the drug and will not interfere with the possibility of conception since ovulatory cycles persist in some cases for six months after drug withdrawal. If conception occurs during therapy, treatment should be discontinued as soon as pregnancy is confirmed to limit foetal exposure to the drug.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.

Lactation

In rats, cabergolineand/or its metabolites are excreted in milk. No information is available on 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, cabergolineshould not be administered to mothers with hyperprolactinemic disorders who wish to breast-feed their infants.

4.7 Effects on ability to drive and use machines

Cabergoline reduces blood pressure, which may impair the reactions of certain patients. This should be taken into account in situations requiring intense awareness, such as when driving a car or operating machinery.

Patients being treated with cabergoline and presenting with somnolence 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) unless patients have overcome such experiences ofsomnolence (see section 4.4).

4.8 Undesirable effects

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).

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: Prolactin inhibitor

ATC code: G02CB03

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.

The prolactin-reducing effect is dose-dependent, starting within 3 hours and remaining for 2-3 weeks. The long-acting effect means that a single dose is generally sufficient to stop the initiation of milk secretion. In treatment of hyperprolactinaemia, the serum prolactin levels are generally normalised within two to four weeks of the optimal dose being attained. Prolactin can still be significantly reduced several months after withdrawal of the treatment.

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-8ß-carboxy-ergoline, which accounts for 4-6% 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 79-115 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.

Linearity/Non-linearity

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 post-implantation 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).

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 species (rodents) with a specific hormonal physiology different to man.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Anhydrous lactose

L-Leucin

Magnesium stearate (E572)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Store in the original package in order to protect from moisture. The drying capsule with silica gel must not be removed from the bottle.

6.5 Nature and contents of container

Brown glass bottles (type III) that contain a desiccation capsule with silica gel. The brown glass bottle has an induction-sealed childproof aluminium membrane and a childproof HDPE top. External box.

Packaging sizes: 2, 8, 14, 15, 16, 20, 28, 30, 32, 40, 48, 50, 60, 90, 96, 100 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

<[To be completed nationally]>

8 MARKETING AUTHORISATION NUMBER

<[To be completed nationally]>

9 DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

<[To be completed nationally]>

10 DATE OF REVISION OF SUMMARY OF PRODUCT CHARACTERISTICS

9 November 2011