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• Cabergoline ratiopharm 0.5 mg tablet ENG SmPC

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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 with known effect: lactose 75.8 mg

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet

White oval-shaped flat bevelled tablets. Each tablet is scored on one side and has „CBG“ on one side and „0.5“ on the other side of the breakline.

The tablet can be divided into equal doses.

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

Posology

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.

Patients with hepatic or renal dysfunction

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

Paediatric population

The safety and efficacy of cabergoline in children and adolescents less than 16 years of age have not been established.

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.

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

• Hypersensitivity to the active substance, any ergot alkaloid or to any of the excipients listed in section 6.1

• History of pulmonary, pericardial and retroperitoneal fibrotic disorders

• 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.

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. 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 5-HT_2Breceptor, 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.

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-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. 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.

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.

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 Interaction 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 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 abnormality (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 should only be used during pregnancy if clearly indicated and after an accurate benefit/risk evaluation (see section 4.4 – 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.

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.

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.

Breastfeeding

In rats, cabergolineand/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, 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 should be careful when performing actions which require fast and accurate reaction during treatment initiation.

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) untilsuch episodes and somnolence have resolved (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).

¹ Very common in patients treated for hyperprolactinaemic disorders; Common in patients treated for inhibition/suppression of lactation

² Common in patients treated for hyperprolactinaemic disorders; Uncommon in patients treated for inhibition/suppression of lactation

³ Very common in patients treated for hyperprolactinaemic disorders; Uncommon in patients treated for inhibition/suppression 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 4.4).

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 national reporting system listed in Appendix V.

4.9 Overdose

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.

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

Do not store above 25 °C.

Store in the original package in order to protect from moisture. The drying bag 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 bag with silica gel. The brown glass bottle has an induction-sealed childproof aluminium membrane and a childproof PP cap. 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

10/2015

<[To be completed nationally]>