Cabergoline 1a Farma
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SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
Cabergoline 1A Farma, 0,5 mg, tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 0,5 mg cabergoline.
Excipient(s):
Each tablet contains 75, 9 mg anhydrous lactose
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL form
Tablet
White, oval, uncoated, biconvex tablet, scored and debossed with “C 1/2“ on one side
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.
The maximum dose is 3 mg cabergoline per day.
Treatment of hyperprolactinaemic disorders.
The recommended initial dosage of cabergoline is 0.5 mg per week given in one (single 0.5 mg) or two (separate 0.25 mg) doses (e.g. on Monday and Thursday) per week. The weekly dose should be increased gradually, preferably by adding 0.5 mg 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 cabergoline up to 4.5 mg cabergoline per week have been used in hyperprolactinaemic patients.
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 per week are to be given since the tolerability of doses greater than 1 mg 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.
Inhibition of lactation
Cabergoline should be administered within the first 24 hours post-partum. The recommended therapeutic dosage is 1mg cabergoline given as a single dose.
Use in patients with hepatic or renal dysfunction
For patients with severe hepatic insufficiency or 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 children or adolescents of less than 16 years of age.
Use in the elderly
As a consequence of the indications for which this strength of cabergoline is presently proposed, experience in the elderly is very limited. Available data do not indicate a special risk.
4.3 Contraindications
Hypersensitivity to cabergoline, other ergot alkaloids or to any of the excipients.
Pre-eclampsia, eclampsia.
Post-partum hypertension or uncontrolled hypertension.
Severely impaired liver function.
History of adverse pulmonary reactions, such as pleuritis and fibrosis, associated with use of dopamine agonists.
For long-term treatment: Evidence of cardiac valvulopathy as determined by pre-treatment echocardiography.
History of psychosis or risk of post partum psychosis.
4.4 Special warnings and precautions for use
General
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.
The assessment of safety and efficacy of cabergoline is limited in patients with renal and hepatic disease. As with other ergot alkaloids, cabergoline should be given with caution to subjects with cardiovascular disease, hypotension, Raynaud's syndrome, peptic ulcer or gastrointestinal bleeding.
The effects of alcohol on overall tolerability of cabergoline are currently unknown.
Symptomatic hypotension can occur within 6 hours following administration of cabergoline: particular attention should be paid when administering cabergoline concomitantly with other medicical products known to lower blood pressure. Because of its elimination half-life hypotensive effects may persist for a few days after cessation of therapy. Monitoring of treatment with regular checks of blood pressure is recommended in the first 3-4 days after initiation of treatment.
Low blood pressure (≥ 20 mmHg systolic and ≥ 10 mmHg diastolic) has been reported in the 3-4 days following a single dose of 1 mg cabergoline in post-partum studies. The undesirable effects generally occur in the first two weeks, and then decline or disappear. 3% of the patients had their treatment discontinued on account of the undesirable effects.
Treatment of hyperprolactinaemic disorders
Since hyperprolactinaemia with amenorrhoea and infertility may be associated with pituitary tumours, the underlying cause of the hyperprolactinaemia should be investigated before treatment with cabergoline is commenced.
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.
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.
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 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:
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Pleuro-pulmonary disease such as dyspnoea, shortness of breath, persistent cough or chest pain.
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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.
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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 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, Xray, 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.
CNS
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 during treatment with cabergoline (se section 4.7). Furthermore a reduction of dosage or termination of therapy may be considered.
Pathological gambling, increased libido and hypersexuality have been reported in patients treated with dopamine agonists for Parkinson's disease, including cabergoline.
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.
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 interaction
Concomitant use not recommended
Elevated plasma levels of bromocriptine have been observed in combination with macrolide antibiotics (such as erythromycin). Effects of macrolide antibiotics on cabergoline’s plasma levels when administered simultaneously have not been studied. The combination should be avoided, as it may result in elevated cabergoline plasma levels.
Cabergoline acts through direct stimulation of dopamine receptors. Consequently, it should not be combined with medicinal products with a dopamine antagonistic effect (such as phenothiazines, butyrophenones, thioxanthenes, metoclopramide).
No information is available about possible interactions between cabergoline and other ergot alkaloids. Therefore, long-term treatment with cabergoline is not advised in combination with these medicinal products.
Precautions
Interactions with other medicinal products that reduce blood pressure should be taken into consideration.
No pharmacokinetic interaction with levodopa or selegiline was observed in the studies carried out in parkinsonian patients. Pharmacokinetic interactions with other medicinal products cannot be predicted based on available information about the metabolism of cabergoline.
4.6 Pregnancy and lactation
Pregnancy
Before cabergoline administration, pregnancy should be excluded and after treatment should be prevented for at least one month.
Cabergoline has been shown to cross the placenta in rats. It is not known whether this occurs also in humans. Data on a limited number of pregnancies (n=100), generally taken during the first 8 weeks after conception, do not indicate cabergoline to be associated with an increased risk of abortion, premature delivery, multiple pregnancy or congenital abnormalities. To date, no other relevant epidemiological data are available. Animal studies indicate no direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or post-natal development.
Because of the limited experience of the use of cabergoline in pregnancy, cabergoline should be withdrawn before a planned pregnancy. If the patient becomes pregnant during treatment, cabergoline shall be immediately withdrawn. During pregnancy, these patients must be carefully monitored for any pregnancy-induced pituitary enlargement.
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 non-hormonal 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 given that ovulatory cycles persist in some patients for 6 months after withdrawal. Should pregnancy occur during treatment, cabergoline is to be discontinued. 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.
Contraception should be continued for at least 4 weeks after stopping cabergoline.
Cabergoline should only be used during pregnancy if clearly indicated.
Lactation
Cabergoline should not be administered to mothers who elect to breastfeed their infants since it prevents lactation. No information is available on the excretion of active substance in maternal milk but in rats cabergoline and/or its metabolites are excreted in the milk.
Lactation should be avoided when taking cabergoline.
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 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 and others at risk of serious injury or death, until such recurrent episodes and somnolence have resolved (see section 4.4)
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 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%.
Low blood pressure (≥ 20 mmHg systolic and ≥ 10 mmHg diastolic) has been reported in the 3-4 days following a single dose of 1 mg cabergoline in post-partum studies.
Hyperprolactinaemic disorders
The undesirable effects generally occur in the first two weeks of therapy, and then decline or disappear. 3% of the patients had their treatment discontinued on account of the undesirable effects.
The following undesirable effects have been observed 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) including isolated reports.
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Psychiatric disorders Common Not known (cannot be estimated from the available data) |
Depression Pathological gambling, increased libido and hypersexuality, generally reversible upon reduction of the dose or treatment discontinuation, hallucinations |
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Nervous system disorders Common Uncommon |
Somnolence, headache, dizziness, paraesthesia, fatigue Episodes of sudden sleep onset |
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Eye disorders Uncommon |
Hemianopia |
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Cardiac disorders Very common Common |
Cardiac valvulopathy (including regurgitation) and related disorders (pericarditis and pericardial effusion) Chest pain (angina), palpitations |
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Vascular disorders Common Uncommon Rare |
Orthostatic hypotension and hypotension Nose bleeding Hot flushes, syncope |
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Respiratory, thoracic and mediastinal disorders Not known (cannot be estimated from the available data) |
Symptomatic pleural effusion/pulmonary fibrosis/pleuritis |
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Gastrointestinal disorders Common |
Nausea, vomiting, gastric pains, dyspepsia, gastritis, constipation |
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Skin and subcutaneous tissue disorders Common Not known (cannot be estimated from the available data) |
Facial redness Alopecia |
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Musculoskeletal, connective tissue and bone disorders Rare |
Cramp in fingers and calves |
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Reproductive system and breast disorders Common |
Breast pain |
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Investigations Uncommon |
Decrease in haemoglobin in amenorrhoeic women after menses resumption |
Post-marketing surveillance (including treatment with different strengths in Parkinson’s disease)
Cabergoline is associated with somnolence and has been associated uncommonly with excessive daytime somnolence and sudden sleep onset episodes.
Patients treated with dopamine agonists for treatment of Parkinson’s disease, including cabergoline, especially at high doses, have been reported as showing pathological gambling, increased libido and hypersexuality, generally reversible upon reduction of the dose or treatment discontinuation.
4.9 Overdose
There is no clinical experience of overdosing, but observations from animal experiments suggest that symptoms resulting from overstimulation of dopamine receptors can be expected, such as nausea, vomiting, reduced blood pressure, confusion/psychosis or hallucinations. Where indicated, measures must be taken to restore blood pressure. In addition, with pronounced symptoms from the CNS (hallucinations), administration of a dopamine antagonist can be necessary.
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 normalized 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 altogether account 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 0.5 mg cabergoline dose.
Ten days after administration about 18% and 72% of the dose is recovered in urine and in 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
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 prolactin secretion in species (rodents) with a specific hormonal physiology different to man.
Preclinical safety studies of cabergoline indicate a large safety margin for this compound in rodents and in monkeys, as well as a lack of teratogenic, mutagenic or carcinogenic potential.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose anhydrous,
L-Leucine
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
After first opening: 3 months.
6.4 Special precautions for storage
Keep the bottle tightly closed in order to protect from light and moisture.
6.5 Nature and contents of container
Amber glass bottle with LDPE cap, and desiccant: 2, 4, 8, 30 and 90 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7. MARKETING AUTHORISATION HOLDER
[To be completed nationally]
8. MARKETING AUTHORISATION NUMBER(S)
[To be completed nationally]
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
2010-09-22
10. DATE OF REVISION OF THE TEXT
2010-09-22